Information

13.5: Cancer Immunobiology and Immunotherapy - Biology

13.5: Cancer Immunobiology and Immunotherapy - Biology



We are searching data for your request:

Forums and discussions:
Manuals and reference books:
Data from registers:
Wait the end of the search in all databases.
Upon completion, a link will appear to access the found materials.

skills to develop

  • Explain how the adaptive specific immune response responds to tumors
  • Discuss the risks and benefits of tumor vaccines

Cancer involves a loss of the ability of cells to control their cell cycle, the stages each eukaryotic cell goes through as it grows and then divides. When this control is lost, the affected cells rapidly divide and often lose the ability to differentiate into the cell type appropriate for their location in the body. In addition, they lose contact inhibition and can start to grow on top of each other. This can result in formation of a tumor. It is important to make a distinction here: The term “cancer” is used to describe the diseases resulting from loss of cell-cycle regulation and subsequent cell proliferation. But the term “tumor” is more general. A “tumor” is an abnormal mass of cells, and a tumor can be benign (not cancerous) or malignant (cancerous).

Traditional cancer treatment uses radiation and/or chemotherapy to destroy cancer cells; however, these treatments can have unwanted side effects because they harm normal cells as well as cancer cells. Newer, promising therapies attempt to enlist the patient’s immune system to target cancer cells specifically. It is known that the immune system can recognize and destroy cancerous cells, and some researchers and immunologists also believe, based on the results of their experiments, that many cancers are eliminated by the body’s own defenses before they can become a health problem. This idea is not universally accepted by researchers, however, and needs further investigation for verification.

Cell-Mediated Response to Tumors

Cell-mediated immune responses can be directed against cancer cells, many of which do not have the normal complement of self-proteins, making them a target for elimination. Abnormal cancer cells may also present tumor antigens. These tumor antigens are not a part of the screening process used to eliminate lymphocytes during development; thus, even though they are self-antigens, they can stimulate and drive adaptive immune responses against abnormal cells.

Presentation of tumor antigens can stimulate naïve helper T cells to become activated by cytokines such as IL-12 and differentiate into TH1 cells. TH1 cells release cytokines that can activate natural killer (NK) cells and enhance the killing of activated cytotoxic T cells. Both NK cells and cytotoxic T cells can recognize and target cancer cells, and induce apoptosis through the action of perforins and granzymes. In addition, activated cytotoxic T cells can bind to cell-surface proteins on abnormal cells and induce apoptosis by a second killing mechanism called the CD95 (Fas) cytotoxic pathway.

Despite these mechanisms for removing cancerous cells from the body, cancer remains a common cause of death. Unfortunately, malignant tumors tend to actively suppress the immune response in various ways. In some cancers, the immune cells themselves are cancerous. In leukemia, lymphocytes that would normally facilitate the immune response become abnormal. In other cancers, the cancerous cells can become resistant to induction of apoptosis. This may occur through the expression of membrane proteins that shut off cytotoxic T cells or that induce regulatory T cells that can shut down immune responses.

The mechanisms by which cancer cells alter immune responses are still not yet fully understood, and this is a very active area of research. As scientists’ understanding of adaptive immunity improves, cancer therapies that harness the body’s immune defenses may someday be more successful in treating and eliminating cancer.

Exercise (PageIndex{1})

  1. How do cancer cells suppress the immune system?
  2. Describe how the immune system recognizes and destroys cancer cells.

There are two types of cancer vaccines: preventive and therapeutic. Preventive vaccines are used to prevent cancer from occurring, whereas therapeutic vaccines are used to treat patients with cancer. Most preventive cancer vaccines target viral infections that are known to lead to cancer. These include vaccines against human papillomavirus (HPV)and hepatitis B, which help prevent cervical and liver cancer, respectively.

Most therapeutic cancer vaccines are in the experimental stage. They exploit tumor-specific antigens to stimulate the immune system to selectively attack cancer cells. Specifically, they aim to enhance TH1 function and interaction with cytotoxic T cells, which, in turn, results in more effective attack on abnormal tumor cells. In some cases, researchers have used genetic engineering to develop antitumor vaccines in an approach similar to that used for DNA vaccines (see Micro Connections: DNA vaccines). The vaccine contains a recombinant plasmid with genes for tumor antigens; theoretically, the tumor gene would not induce new cancer because it is not functional, but it could trick the immune system into targeting the tumor gene product as a foreign invader.

The first FDA-approved therapeutic cancer vaccine was sipuleucel-T (Provenge), approved in 2010 to treat certain cases of prostate cancer.1 This unconventional vaccine is custom designed using the patient’s own cells. APCs are removed from the patient and cultured with a tumor-specific molecule; the cells are then returned to the patient. This approach appears to enhance the patient’s immune response against the cancer cells. Another therapeutic cancer vaccine (talimogene laherparepvec, also called T-VEC or Imlygic) was approved by the FDA in 2015 for treatment of melanoma, a form of skin cancer. This vaccine contains a virus that is injected into tumors, where it infects and lyses the tumor cells. The virus also induces a response in lesions or tumors besides those into which the vaccine is injected, indicating that it is stimulating a more general (as opposed to local) antitumor immune response in the patient.

Exercise (PageIndex{2})

  1. Explain the difference between preventative and therapeutic cancer vaccines.
  2. Describe at least two different approaches to developing therapeutic anti-cancer vaccines.

USING VIRUSES TO CURE CANCER

Viruses typically destroy the cells they infect—a fact responsible for any number of human diseases. But the cell-killing powers of viruses may yet prove to be the cure for some types of cancer, which is generally treated by attempting to rid the body of cancerous cells. Several clinical trials are studying the effects of viruses targeted at cancer cells. Reolysin, a drug currently in testing phases, uses reoviruses (respiratory enteric orphan viruses) that can infect and kill cells that have an activated Ras-signaling pathway, a common mutation in cancerous cells. Viruses such as rubeola (the measles virus) can also be genetically engineered to aggressively attack tumor cells. These modified viruses not only bind more specifically to receptors overexpressed on cancer cells, they also carry genes driven by promoters that are only turned on within cancer cells. Herpesvirus and others have also been modified in this way.

Key Concepts and Summary

  • Cancer results from a loss of control of the cell cycle, resulting in uncontrolled cell proliferation and a loss of the ability to differentiate.
  • Adaptive and innate immune responses are engaged by tumor antigens, self-molecules only found on abnormal cells. These adaptive responses stimulate helper T cells to activate cytotoxic T cells and NK cells of innate immunity that will seek and destroy cancer cells.
  • New anticancer therapies are in development that will exploit natural adaptive immunity anticancer responses. These include external stimulation of cytotoxic T cells and therapeutic vaccines that assist or enhance the immune response.
  1. 1 National Institutes of Health, National Cancer Institute. "Cancer Vaccines." http://www.cancer.gov/about-cancer/c...-fact-sheet#q8. Accessed on May 20, 2016.

Contributor

  • Nina Parker, (Shenandoah University), Mark Schneegurt (Wichita State University), Anh-Hue Thi Tu (Georgia Southwestern State University), Philip Lister (Central New Mexico Community College), and Brian M. Forster (Saint Joseph’s University) with many contributing authors. Original content via Openstax (CC BY 4.0; Access for free at https://openstax.org/books/microbiology/pages/1-introduction)


13.5: Cancer Immunobiology and Immunotherapy - Biology

All articles published by MDPI are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by MDPI, including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited.

Feature Papers represent the most advanced research with significant potential for high impact in the field. Feature Papers are submitted upon individual invitation or recommendation by the scientific editors and undergo peer review prior to publication.

The Feature Paper can be either an original research article, a substantial novel research study that often involves several techniques or approaches, or a comprehensive review paper with concise and precise updates on the latest progress in the field that systematically reviews the most exciting advances in scientific literature. This type of paper provides an outlook on future directions of research or possible applications.

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to authors, or important in this field. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.


19.5 Cancer Immunobiology and Immunotherapy

Cancer involves a loss of the ability of cells to control their cell cycle , the stages each eukaryotic cell goes through as it grows and then divides. When this control is lost, the affected cells rapidly divide and often lose the ability to differentiate into the cell type appropriate for their location in the body. In addition, they lose contact inhibition and can start to grow on top of each other. This can result in formation of a tumor . It is important to make a distinction here: The term “ cancer ” is used to describe the diseases resulting from loss of cell-cycle regulation and subsequent cell proliferation. But the term “tumor” is more general. A “tumor” is an abnormal mass of cells, and a tumor can be benign (not cancerous) or malignant (cancerous).

Traditional cancer treatment uses radiation and/or chemotherapy to destroy cancer cells however, these treatments can have unwanted side effects because they harm normal cells as well as cancer cells. Newer, promising therapies attempt to enlist the patient’s immune system to target cancer cells specifically. It is known that the immune system can recognize and destroy cancerous cells, and some researchers and immunologists also believe, based on the results of their experiments, that many cancers are eliminated by the body’s own defenses before they can become a health problem. This idea is not universally accepted by researchers, however, and needs further investigation for verification.

Cell-Mediated Response to Tumors

Cell-mediated immune responses can be directed against cancer cells, many of which do not have the normal complement of self-proteins, making them a target for elimination. Abnormal cancer cells may also present tumor antigen s. These tumor antigens are not a part of the screening process used to eliminate lymphocytes during development thus, even though they are self-antigens, they can stimulate and drive adaptive immune responses against abnormal cells.

Presentation of tumor antigens can stimulate naïve helper T cells to become activated by cytokines such as IL-12 and differentiate into TH1 cell s. TH1 cells release cytokines that can activate natural killer (NK) cells and enhance the killing of activated cytotoxic T cell s. Both NK cell s and cytotoxic T cells can recognize and target cancer cells, and induce apoptosis through the action of perforin s and granzyme s. In addition, activated cytotoxic T cells can bind to cell-surface proteins on abnormal cells and induce apoptosis by a second killing mechanism called the CD95 (Fas) cytotoxic pathway .

Despite these mechanisms for removing cancerous cells from the body, cancer remains a common cause of death. Unfortunately, malignant tumors tend to actively suppress the immune response in various ways. In some cancers, the immune cells themselves are cancerous. In leukemia , lymphocytes that would normally facilitate the immune response become abnormal. In other cancers, the cancerous cells can become resistant to induction of apoptosis . This may occur through the expression of membrane proteins that shut off cytotoxic T cells or that induce regulatory T cells that can shut down immune responses.

The mechanisms by which cancer cells alter immune responses are still not yet fully understood, and this is a very active area of research. As scientists’ understanding of adaptive immunity improves, cancer therapies that harness the body’s immune defenses may someday be more successful in treating and eliminating cancer.

Check Your Understanding

  • How do cancer cells suppress the immune system?
  • Describe how the immune system recognizes and destroys cancer cells.

Cancer Vaccines

There are two types of cancer vaccines : preventive and therapeutic. Preventive vaccines are used to prevent cancer from occurring, whereas therapeutic vaccines are used to treat patients with cancer. Most preventive cancer vaccines target viral infections that are known to lead to cancer. These include vaccines against human papillomavirus (HPV) and hepatitis B , which help prevent cervical and liver cancer, respectively.

Most therapeutic cancer vaccines are in the experimental stage. They exploit tumor-specific antigens to stimulate the immune system to selectively attack cancer cells. Specifically, they aim to enhance TH1 function and interaction with cytotoxic T cells, which, in turn, results in more effective attack on abnormal tumor cells. In some cases, researchers have used genetic engineering to develop antitumor vaccines in an approach similar to that used for DNA vaccines (see Micro Connections: DNA vaccines). The vaccine contains a recombinant plasmid with genes for tumor antigens theoretically, the tumor gene would not induce new cancer because it is not functional, but it could trick the immune system into targeting the tumor gene product as a foreign invader.

The first FDA-approved therapeutic cancer vaccine was sipuleucel-T (Provenge) , approved in 2010 to treat certain cases of prostate cancer . 17 This unconventional vaccine is custom designed using the patient’s own cells. APCs are removed from the patient and cultured with a tumor-specific molecule the cells are then returned to the patient. This approach appears to enhance the patient’s immune response against the cancer cells. Another therapeutic cancer vaccine (talimogene laherparepvec, also called T-VEC or Imlygic ) was approved by the FDA in 2015 for treatment of melanoma , a form of skin cancer. This vaccine contains a virus that is injected into tumors, where it infects and lyses the tumor cells. The virus also induces a response in lesions or tumors besides those into which the vaccine is injected, indicating that it is stimulating a more general (as opposed to local) antitumor immune response in the patient.

Check Your Understanding

  • Explain the difference between preventative and therapeutic cancer vaccines.
  • Describe at least two different approaches to developing therapeutic anti-cancer vaccines.

Micro Connections

Using Viruses to Cure Cancer

Viruses typically destroy the cells they infect—a fact responsible for any number of human diseases. But the cell-killing powers of viruses may yet prove to be the cure for some types of cancer, which is generally treated by attempting to rid the body of cancerous cells. Several clinical trials are studying the effects of viruses targeted at cancer cells. Reolysin , a drug currently in testing phases, uses reoviruses (respiratory enteric orphan viruses) that can infect and kill cells that have an activated Ras-signaling pathway, a common mutation in cancerous cells. Viruses such as rubeola (the measles virus) can also be genetically engineered to aggressively attack tumor cells. These modified viruses not only bind more specifically to receptors overexpressed on cancer cells, they also carry genes driven by promoters that are only turned on within cancer cells. Herpesvirus and others have also been modified in this way.


Immunobiology and immunotherapy

This section aims to enrich the communication between basic biological and immunological sciences and the clinical investigation arena.

As immunology has evolved to be a central discipline connected to a wide range of therapeutic areas, the number and diversity of platform technologies has also increased, spanning small molecules, biologics, microbial vectors and cells. Such levels of activity require appropriate means to share new knowledge and to catalyze the development of the field. This section aims to provide such a platform and welcomes submissions across all disciplines, including inflammation, autoimmunity, transplantation, metabolic disorders.

The section was founded with the Society for Immunotherapy of Cancer (SITC) under the title "Tumor immunology and biological cancer therapy" and Edited by Pedro Romero.

Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

Activator protein-1 (AP1), a c-Fos–JUN transcription factor complex, mediates many cytobiological processes. c-Fos has been implicated in immunoglobulin (Ig)E activation of mast cells (MCs) via high-affinity I.

Authors: Hui-Na Wang, Kunmei Ji, Li-Na Zhang, Chu-Chu Xie, Wei-Yong Li, Zhen-Fu Zhao and Jia-Jie Chen

Citation: Journal of Translational Medicine 2021 19 :261

Published on: 15 June 2021

HDAC4 induces the development of asthma by increasing Slug-upregulated CXCL12 expression through KLF5 deacetylation

Asthma is a frequently occurring respiratory disease with an increasing incidence around the world. Airway inflammation and remodeling are important contributors to the occurrence of asthma. We conducted this .

Authors: Wendi Wei, Weida Chen and Naifeng He

Citation: Journal of Translational Medicine 2021 19 :258

Published on: 12 June 2021

Cellular and molecular mediators of lymphangiogenesis in inflammatory bowel disease

Recent studies reporting the intricate crosstalk between cellular and molecular mediators and the lymphatic endothelium in the development of inflammatory bowel diseases (IBD) suggest altered inflammatory cell.

Authors: Dickson Kofi Wiredu Ocansey, Bing Pei, Xinwei Xu, Lu Zhang, Chinasa Valerie Olovo and Fei Mao

Citation: Journal of Translational Medicine 2021 19 :254

Published on: 10 June 2021

Potential roles of N6-methyladenosine (m6A) in immune cells

N6-methyl-adenosine (m6A) is one of the most common internal modifications on RNA molecules present in mammalian cells. Deregulation of m6A modification has been recently implicated in many types of human dise.

Authors: Chang Liu, Zhe Yang, Rong Li, Yanju Wu, Ming Chi, Shuting Gao, Xun Sun, Xin Meng and Biao Wang

Citation: Journal of Translational Medicine 2021 19 :251

Characterization of terminal-ileal and colonic Crohn’s disease in treatment-naïve paediatric patients based on transcriptomic profile using logistic regression

Inflammatory bowel disease (IBD) is a chronic and idiopathic inflammatory disorder of the gastrointestinal tract and comprises ulcerative colitis (UC) and Crohn’s disease (CD). Crohn’s disease can affect any p.

Authors: Ilkyu Park, Jaeeun Jung, Sugi Lee, Kunhyang Park, Jea-Woon Ryu, Mi-Young Son, Hyun-Soo Cho and Dae-Soo Kim

Citation: Journal of Translational Medicine 2021 19 :250

Automated tumor proportion scoring for PD-L1 expression based on multistage ensemble strategy in non-small cell lung cancer

Programmed cell death ligand-1 (PD-L1) expression is a promising biomarker for identifying treatment related to non-small cell lung cancer (NSCLC). Automated image analysis served as an aided PD-L1 scoring too.

Authors: Boju Pan, Yuxin Kang, Yan Jin, Lin Yang, Yushuang Zheng, Lei Cui, Jian Sun, Jun Feng, Yuan Li, Lingchuan Guo and Zhiyong Liang

Citation: Journal of Translational Medicine 2021 19 :249

Interleukin-24 regulates mucosal remodeling in inflammatory bowel diseases

Recently, increased interleukin (IL)-24 expression has been demonstrated in the colon biopsies of adult patients with inflammatory bowel disease (IBD). However, the role of IL-24 in the pathomechanism of IBD i.

Authors: Anna Ónody, Apor Veres-Székely, Domonkos Pap, Réka Rokonay, Beáta Szebeni, Erna Sziksz, Franz Oswald, Gábor Veres, Áron Cseh, Attila J. Szabó and Ádám Vannay

Citation: Journal of Translational Medicine 2021 19 :237

Identification of immune subtypes of cervical squamous cell carcinoma predicting prognosis and immunotherapy responses

The main limitation of current immune checkpoint inhibitors (ICIs) in the treatment of cervical cancer comes from the fact that it benefits only a minority of patients. The study aims to develop a classificati.

Authors: Yimin Li, Shun Lu, Shubin Wang, Xinhao Peng and Jinyi Lang

Citation: Journal of Translational Medicine 2021 19 :222

Extracellular vesicle-derived miRNA as a novel regulatory system for bi-directional communication in gut-brain-microbiota axis

The gut-brain-microbiota axis (GBMAx) coordinates bidirectional communication between the gut and brain, and is increasingly recognized as playing a central role in physiology and disease. MicroRNAs are import.

Authors: Liang Zhao, Yingze Ye, Lijuan Gu, Zhihong Jian, Creed M. Stary and Xiaoxing Xiong

Citation: Journal of Translational Medicine 2021 19 :202

Metformin ameliorates scleroderma via inhibiting Th17 cells and reducing mTOR-STAT3 signaling in skin fibroblasts

Scleroderma is an autoimmune disease that causes dermal fibrosis. It occurs when collagen accumulates in tissue as a result of persistent inflammation. Th17 cells and pro-inflammatory cytokines such as IL-1β.

Authors: Jeonghyeon Moon, Seon-yeong Lee, Jeong Won Choi, A Ram Lee, Jin Hee Yoo, Su-Jin Moon, Sung-Hwan Park and Mi-La Cho

Citation: Journal of Translational Medicine 2021 19 :192

The Correction to this article has been published in Journal of Translational Medicine 2021 19:266

A combination of the percentages of IFN-γ + CD4 + T cells and granzyme B + CD19 + B cells is associated with acute hepatic rejection: a case control study

T cells and B cells play a key role in alloimmune responses. We aimed to characterize the shift of T cell subsets and B cell subsets during acute hepatic rejection, and further determine whether they could ser.

Authors: Ji-Qiao Zhu, Jing Wang, Xian-Liang Li, Wen-Li Xu, Shao-cheng Lv, Xin Zhao, Ren Lang and Qiang He

Citation: Journal of Translational Medicine 2021 19 :187

Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant prop.

Authors: Lydia Ntari, Christoforos Nikolaou, Ksanthi Kranidioti, Dimitra Papadopoulou, Eleni Christodoulou-Vafeiadou, Panagiotis Chouvardas, Florian Meier, Christina Geka, Maria C. Denis, Niki Karagianni and George Kollias

Citation: Journal of Translational Medicine 2021 19 :165

Published on: 23 April 2021

Pirfenidone attenuates synovial fibrosis and postpones the progression of osteoarthritis by anti-fibrotic and anti-inflammatory properties in vivo and in vitro

Osteoarthritis (OA) is a disease of the entire joint involving synovial fibrosis and inflammation. Pathological changes to the synovium can accelerate the progression of OA. Pirfenidone (PFD) is a potent anti-.

Authors: Qilu Wei, Ning Kong, Xiaohui Liu, Run Tian, Ming Jiao, Yiyang Li, Huanshuai Guan, Kunzheng Wang and Pei Yang

Citation: Journal of Translational Medicine 2021 19 :157

Published on: 19 April 2021

Effect of antibiotic-induced intestinal dysbacteriosis on bronchopulmonary dysplasia and related mechanisms

Modification of the gut microbiota by antibiotics may influence the disease susceptibility and immunological responses. Infants in the neonatal intensive care unit (NICU) subjected to frequent antibiotics and .

Authors: Xiao Ran, Yu He, Qing Ai and Yuan Shi

Citation: Journal of Translational Medicine 2021 19 :155

Published on: 16 April 2021

Identification of 4 immune cells and a 5-lncRNA risk signature with prognosis for early-stage lung adenocarcinoma

Lung cancer is the most common cancer and cause of cancer‐related mortality worldwide, increasing evidence indicated that there was a significant correlation between tumors and the long non‐coding RNAs (lncRNA.

Authors: Lan Mu, Ke Ding, Ranran Tu and Wei Yang

Citation: Journal of Translational Medicine 2021 19 :127

Published on: 26 March 2021

Cerebrospinal fluid cells immune landscape in multiple sclerosis

Multiple Sclerosis (MS) is a potentially devastating autoimmune neurological disorder, which characteristically induces demyelination of white matter in the brain and spinal cord.

Authors: Zijian Li, Yongchao Liu, Aili Jia, Yueran Cui and Juan Feng

Citation: Journal of Translational Medicine 2021 19 :125

Published on: 25 March 2021

Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) induces uncontrolled and self-amplified pulmonary inflammation, and has high morbidity and mortality rates in critically ill patients. In rece.

Authors: Jiucui Li, Kongmiao Lu, Fenglan Sun, Shanjuan Tan, Xiao Zhang, Wei Sheng, Wanming Hao, Min Liu, Weihong Lv and Wei Han

Citation: Journal of Translational Medicine 2021 19 :96

Published on: 2 March 2021

High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study

Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squam.

Authors: Issei Sumiyoshi, Takahiro Okabe, Shinsaku Togo, Haruhi Takagi, Hiroaki Motomura, Yusuke Ochi, Naoko Shimada, Mizuki Haraguchi, Rina Shibayama, Yuichi Fujimoto, Junko Watanabe, Moe Iwai, Kotaro Kadoya, Shin-ichiro Iwakami and Kazuhisa Takahashi

Citation: Journal of Translational Medicine 2021 19 :92

Published on: 28 February 2021

Niclosamide suppresses the expansion of follicular helper T cells and alleviates disease severity in two murine models of lupus via STAT3

Autoantibody production against endogenous cellular components is pathogenic feature of systemic lupus erythematosus (SLE). Follicular helper T (TFH) cells aid in B cell differentiation into autoantibody-producin.

Authors: Se Gwang Jang, Jaeseon Lee, Seung-Min Hong, Young-Seok Song, Min Jun Kim, Seung-Ki Kwok, Mi-La Cho and Sung-Hwan Park

Citation: Journal of Translational Medicine 2021 19 :86

Published on: 25 February 2021

Identification of key biomarkers and immune infiltration in systemic lupus erythematosus by integrated bioinformatics analysis

Systemic lupus erythematosus (SLE) is a multisystemic, chronic inflammatory disease characterized by destructive systemic organ involvement, which could cause the decreased functional capacity, increased morbi.

Authors: Xingwang Zhao, Longlong Zhang, Juan Wang, Min Zhang, Zhiqiang Song, Bing Ni and Yi You

Citation: Journal of Translational Medicine 2021 19 :35

Published on: 19 January 2021

The Correction to this article has been published in Journal of Translational Medicine 2021 19:64

Model based on five tumour immune microenvironment-related genes for predicting hepatocellular carcinoma immunotherapy outcomes

Although the tumour immune microenvironment is known to significantly influence immunotherapy outcomes, its association with changes in gene expression patterns in hepatocellular carcinoma (HCC) during immunot.

Authors: Xinyu Gu, Jun Guan, Jia Xu, Qiuxian Zheng, Chao Chen, Qin Yang, Chunhong Huang, Gang Wang, Haibo Zhou, Zhi Chen and Haihong Zhu

Citation: Journal of Translational Medicine 2021 19 :26

Published on: 6 January 2021

Development of nomogram based on immune-related gene FGFR4 for advanced non-small cell lung cancer patients with sensitivity to immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs) have become a frontier in the field of clinical technology for advanced non-small cell lung cancer (NSCLC). Currently, the predictive biomarker of ICIs mainly including the .

Authors: Li Wang, Zhixuan Ren, Bentong Yu and Jian Tang

Citation: Journal of Translational Medicine 2021 19 :22

Published on: 6 January 2021

Validation of a method evaluating T cell metabolic potential in compliance with ICH Q2 (R1)

Metabolic cell features are able to give reliable information on cell functional state. Thus, metabolic potential assessment of T cells in malignancy setting represents a promising area, especially in adoptive.

Authors: Patricia Mercier-Letondal, Chrystel Marton, Yann Godet and Jeanne Galaine

Citation: Journal of Translational Medicine 2021 19 :21

Published on: 6 January 2021

Three hematologic/immune system-specific expressed genes are considered as the potential biomarkers for the diagnosis of early rheumatoid arthritis through bioinformatics analysis

Rheumatoid arthritis (RA) is the most common chronic autoimmune connective tissue disease. However, early RA is difficult to diagnose due to the lack of effective biomarkers. This study aimed to identify new b.

Authors: Qi Cheng, Xin Chen, Huaxiang Wu and Yan Du

Citation: Journal of Translational Medicine 2021 19 :18

Published on: 6 January 2021

Immune responses to azacytidine in animal models of inflammatory disorders: a systematic review

Inflammatory disorders like diabetes, systemic lupus erythematodes, inflammatory lung diseases, rheumatoid arthritis and multiple sclerosis, but also rejection of transplanted organs and GvHD, form a major bur.

Authors: Sija Landman, Chiel van der Horst, Piet E. J. van Erp, Irma Joosten, Rob de Vries and Hans J. P. M. Koenen

Citation: Journal of Translational Medicine 2021 19 :11

Published on: 6 January 2021

Regulatory T cells mediated immunomodulation during asthma: a therapeutic standpoint

Asthma is an inflammatory disease of the lung airway network, which is initiated and perpetuated by allergen-specific CD4 + T cells, IgE antibodies, and a massive release of Th2 cytokines. The most common clinical.

Authors: Mohammad Afzal Khan

Citation: Journal of Translational Medicine 2020 18 :456

Published on: 2 December 2020

Positive association of Parkinson’s disease with ankylosing spondylitis: a nationwide population-based study

Ankylosing spondylitis (AS) is characterized by excessive production of inflammatory cytokines. Recent evidence suggests that inflammation underlies the neurodegenerative process of Parkinson’s disease (PD). W.

Authors: Fu-Chiang Yeh, Hsiang-Cheng Chen, Yu-Ching Chou, Cheng-Li Lin, Chia-Hung Kao, Hsin-Yi Lo, Feng-Cheng Liu and Tse-Yen Yang

Citation: Journal of Translational Medicine 2020 18 :455

Published on: 30 November 2020

LMWF5A suppresses cytokine release by modulating select inflammatory transcription factor activity in stimulated PBMC

Dysregulation of transcription and cytokine expression has been implicated in the pathogenesis of a variety inflammatory diseases. The resulting imbalance between inflammatory and resolving transcriptional pro.

Authors: Gregory Thomas, Elizabeth Frederick, Lisa Thompson, Raphael Bar-Or, Yetti Mulugeta, Melissa Hausburg, Michael Roshon, Charles Mains and David Bar-Or

Citation: Journal of Translational Medicine 2020 18 :452

Published on: 30 November 2020

Tespa1 plays a role in the modulation of airway hyperreactivity through the IL-4/STAT6 pathway

Thymocyte-expressed, positive selection-associated 1 (Tespa1) is a critical signaling molecule in thymocyte development. This study aimed to investigate the regulatory effect of Tespa1 on mast cells in the pat.

Authors: Ruhui Yang, Guangli Wang, Lingyun Li, Hanjiang He, Mingzhu Zheng, Linrong Lu and Songquan Wu

Citation: Journal of Translational Medicine 2020 18 :444

Published on: 23 November 2020

Immune landscape of periodontitis unveils alterations of infiltrating immunocytes and molecular networks-aggregating into an interactive web-tool for periodontitis related immune analysis and visualization

Immunity reaction plays an essential role in periodontitis progress and we aim to investigate the underlying regulatory network of immune reactions in periodontitis.

Authors: Xiaoqi Zhang, Qingxuan Wang, Xinyu Yan, Yue Shan, Lu Xing, Minqi Li, Hu Long and Wenli Lai

Citation: Journal of Translational Medicine 2020 18 :438

Published on: 18 November 2020

Conformational changes in myeloperoxidase induced by ubiquitin and NETs containing free ISG15 from systemic lupus erythematosus patients promote a pro-inflammatory cytokine response in CD4 + T cells

Neutrophil extracellular traps (NETs) from patients with systemic lupus erythematosus (SLE) are characterized by lower ubiquitylation and myeloperoxidase (MPO) as a substrate. The structural and functional eff.

Authors: Daniel Alberto Carrillo-Vázquez, Eduardo Jardón-Valadez, Jiram Torres-Ruiz, Guillermo Juárez-Vega, José Luis Maravillas-Montero, David Eduardo Meza-Sánchez, María Lilia Domínguez-López, Jorge Carlos Alcocer Varela and Diana Gómez-Martín

Citation: Journal of Translational Medicine 2020 18 :429

Published on: 11 November 2020

Bronchoalveolar Tregs are associated with duration of mechanical ventilation in acute respiratory distress syndrome

Foxp3 + regulatory T cells (Tregs) play essential roles in immune homeostasis and repair of damaged lung tissue. We hypothesized that patients whose lung injury resolves quickly, as measured by time to liberation .

Authors: Dustin L. Norton, Agathe Ceppe, Miriya K. Tune, Matthew McCravy, Thomas Devlin, M. Bradley Drummond, Shannon S. Carson, Benjamin G. Vincent, Robert S. Hagan, Hong Dang, Claire M. Doerschuk and Jason R. Mock

Citation: Journal of Translational Medicine 2020 18 :427

Published on: 11 November 2020

Hypoxia directed migration of human naïve monocytes is associated with an attenuation of cytokine release: indications for a key role of CCL26

Numerous tissue-derived factors have been postulated to be involved in tissue migration of circulating monocytes. The aim of this study was to evaluate whether a defined hypoxic gradient can induce directed mi.

Authors: Lars Hummitzsch, Rouven Berndt, Matthias Kott, Rene Rusch, Fred Faendrich, Matthias Gruenewald, Markus Steinfath, Martin Albrecht and Karina Zitta

Citation: Journal of Translational Medicine 2020 18 :404

Published on: 21 October 2020

High Smad7 in the early post-operative recurrence of Crohn’s disease

In Crohn’s disease (CD), one of the major inflammatory bowel disease (IBD) in human beings, there is over-expression of Smad7, an intracellular inhibitor of the suppressive cytokine TGF-β1. The aim of this stu.

Authors: Francesca Zorzi, Emma Calabrese, Davide Di Fusco, Elena De Cristofaro, Livia Biancone, Sara Casella, Giampiero Palmieri and Giovanni Monteleone

Citation: Journal of Translational Medicine 2020 18 :395

Published on: 19 October 2020

Rs2476601 in PTPN22 gene in rheumatoid arthritis and periodontitis—a possible interface?

Rheumatoid arthritis (RA) and periodontitis (PD) are proven to share common risk markers, including genetic factors. In the present study we focused on genetic variants in PTPN22 (rs2476601), PADI4 (rs2240340), C.

Authors: Susanne Schulz, Pauline Zimmer, Natalie Pütz, Elisa Jurianz, Hans-Günter Schaller and Stefan Reichert

Citation: Journal of Translational Medicine 2020 18 :389

Published on: 15 October 2020

Assessment of EN-RAGE, sRAGE and EN-RAGE/sRAGE as potential biomarkers in patients with autoimmune hepatitis

Autoimmune hepatitis (AIH) is a liver disease characterized by the autoimmune-induced injury of hepatocytes which can lead to cirrhosis and hepatic failure. The diagnosis and disease management of AIH patients.

Authors: Rui Wu, Yan Liu, Ruyu Yan, Xiaoyu Liu and Liang Duan

Citation: Journal of Translational Medicine 2020 18 :384

Published on: 9 October 2020

Novel single-domain antibodies against the EGFR domain III epitope exhibit the anti-tumor effect

Monoclonal antibodies (mAbs) have been used for cancer therapy. They are large and have some disadvantages limiting their use. Smaller antibody fragments are needed as their alternatives. A fully human single-.

Authors: Tao Chen, Xue Liu, Haifeng Hong and Henry Wei

Citation: Journal of Translational Medicine 2020 18 :376

Published on: 6 October 2020

Localized cytokine responses to total knee arthroplasty and total knee revision complications

The study of localized immune-related factors has proven beneficial for a variety of conditions, and one area of interest in the field of orthopaedics is the impact of implants and localized infections on immu.

Authors: Nicole Prince, Julia A. Penatzer, Matthew J. Dietz and Jonathan W. Boyd

Citation: Journal of Translational Medicine 2020 18 :330

Published on: 31 August 2020

Lactobacillus sakei suppresses collagen-induced arthritis and modulates the differentiation of T helper 17 cells and regulatory B cells

To evaluate the immunomodulatory effect of Lactobacillus sakei in a mouse model of rheumatoid arthritis (RA) and in human immune cells.

Authors: Jooyeon Jhun, Hong Ki Min, Jaeyoon Ryu, Seon-Yeong Lee, Jun-Geol Ryu, Jeong Won Choi, Hyun Sik Na, Seung Yoon Lee, Yunju Jung, Sang-Jun Park, Myeong Soo Park, Bin Kwon, Geun Eog Ji, Mi-La Cho and Sung-Hwan Park

Citation: Journal of Translational Medicine 2020 18 :317

Published on: 15 August 2020

Expression and clinical significance of LAG-3, FGL1, PD-L1 and CD8 + T cells in hepatocellular carcinoma using multiplex quantitative analysis

Fibrinogen-like protein 1 (FGL1)—Lymphocyte activating gene 3 (LAG-3) pathway is a promising immunotherapeutic target and has synergistic effect with programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1).

Authors: Mengzhou Guo, Feifei Yuan, Feng Qi, Jialei Sun, Qianwen Rao, Zhiying Zhao, Peixin Huang, Tingting Fang, Biwei Yang and Jinglin Xia

Citation: Journal of Translational Medicine 2020 18 :306

Published on: 6 August 2020

The establishment of a rheumatoid arthritis primate model in Macaca fascicularis

Rheumatoid arthritis (RA) is a long-term autoimmune disorder that mostly affects the joints and leads to the destruction of cartilage. An RA model in non-human primates is especially useful because of their cl.

Authors: Hyun Sik Na, Seon-yeong Lee, Hong Ki Min, Wan-je Park, Jung-hwan Lee, Ka-hee Cho, Shin-hee Hong, Dae-hoon Kim, Jooyeon Jhun, Jeong-Won Choi, Sung-Min Kim, Seung-Ki Kwok, Mi-La Cho and Sung-Hwan Park

Citation: Journal of Translational Medicine 2020 18 :264

Published on: 30 June 2020

Boning up: amino-bisphophonates as immunostimulants and endosomal disruptors of dendritic cell in SARS-CoV-2 infection

Amino-bisphosphonates such as zoledronic acid (ZA) can possibly ameliorate or prevent severe COVID-19 disease by at least three distinct mechanisms: (1) as immunostimulants which could boost γδ T cell expansio.

Authors: Adam Brufsky, Juan Luis Gomez Marti, Azadeh Nasrazadani and Michael T. Lotze

Citation: Journal of Translational Medicine 2020 18 :261

Published on: 29 June 2020

Evaluation of T-activated proteins as recall antigens to monitor Epstein–Barr virus and human cytomegalovirus-specific T cells in a clinical trial setting

Pools of overlapping synthetic peptides are routinely used for ex vivo monitoring of antigen-specific T-cell responses. However, it is rather unlikely that these peptides match those resulting from naturally p.

Authors: Nina Körber, Uta Behrends, Ulrike Protzer and Tanja Bauer

Citation: Journal of Translational Medicine 2020 18 :242

Published on: 17 June 2020

FTY720 ameliorates GvHD by blocking T lymphocyte migration to target organs and by skin fibrosis inhibition

Fibrosis is the formation of excess connective tissue in an organ or tissue during a reparative or reactive process. Graft-versus-host disease (GvHD) is a medical complication of allogeneic tissue transplantat.

Authors: Jaeyoon Ryu, Jooyeon Jhun, Min-Jung Park, Jin-ah Baek, Se-Young Kim, Keun-Hyung Cho, Jeong-Won Choi, Sung-Hwan Park, Jong Young Choi and Mi-La Cho

Citation: Journal of Translational Medicine 2020 18 :225

Decidual CD8 + T cells exhibit both residency and tolerance signatures modulated by decidual stromal cells

During early pregnancy, tolerance of the semi-allogeneic fetus necessitates comprehensive modifications of the maternal immune system. How decidual CD8 + T (CD8 + dT) cells balance maternal tolerance of the fetus wit.

Authors: Lu Liu, Xixi Huang, Chunfang Xu, Chunqin Chen, Weijie Zhao, Dajin Li, Liping Li, Li Wang and Meirong Du

Citation: Journal of Translational Medicine 2020 18 :221

Accumulation of blood-circulating PD-L1-expressing M-MDSCs and monocytes/macrophages in pretreatment ovarian cancer patients is associated with soluble PD-L1

Previous studies have shown clinical relevance of programmed death-ligand 1 (PD-L1) and soluble PD-L1 (sPD-L1) in human cancers. However, still contradictory results exist. Our aim was evaluation of PD-L1-expr.

Authors: Karolina Okła, Alicja Rajtak, Arkadiusz Czerwonka, Marcin Bobiński, Anna Wawruszak, Rafał Tarkowski, Wiesława Bednarek, Justyna Szumiło and Jan Kotarski

Citation: Journal of Translational Medicine 2020 18 :220

The Correction to this article has been published in Journal of Translational Medicine 2020 18:258

Neutrophil-to-lymphocyte ratio predicts critical illness patients with 2019 coronavirus disease in the early stage

Patients with critical illness due to infection with the 2019 coronavirus disease (COVID-19) show rapid disease progression to acute respiratory failure. The study aimed to screen the most useful predictive fa.

Authors: Jingyuan Liu, Yao Liu, Pan Xiang, Lin Pu, Haofeng Xiong, Chuansheng Li, Ming Zhang, Jianbo Tan, Yanli Xu, Rui Song, Meihua Song, Lin Wang, Wei Zhang, Bing Han, Li Yang, Xiaojing Wang&hellip

Citation: Journal of Translational Medicine 2020 18 :206

Metabolic abnormalities exacerbate Sjögren’s syndrome by and is associated with increased the population of interleukin–17–producing cells in NOD/ShiLtJ mice

Sjögren’s syndrome (SS) is an autoimmune disease mediated by lymphocytic infiltration into exocrine glands, resulting in progressive lacrimal and salivary destruction and dysfunctional glandular secretion. Met.

Authors: Sun-Hee Hwang, Jin-Sil Park, SeungCheon Yang, Kyung-Ah Jung, JeongWon Choi, Seung-Ki Kwok, Sung-Hwan Park and Mi-La Cho

Citation: Journal of Translational Medicine 2020 18 :186

Cytokine network analysis of immune responses before and after autologous dendritic cell and tumor cell vaccine immunotherapies in a randomized trial

In a randomized phase II trial conducted in patients with metastatic melanoma, patient-specific autologous dendritic cell vaccines (DCV) were associated with longer survival than autologous tumor cell vaccines.

Authors: Gabriel I. Nistor and Robert O. Dillman

Citation: Journal of Translational Medicine 2020 18 :176

Published on: 21 April 2020

Simultaneous quantification of natural and inducible regulatory T-cell subsets during interferon-β therapy of multiple sclerosis patients

The mechanisms underlying the therapeutic activity of interferon-β in multiple sclerosis are still not completely understood. In the present study, we evaluated the short and long-term effects of interferon-β .

Authors: Marco Chiarini, Ruggero Capra, Federico Serana, Diego Bertoli, Alessandra Sottini, Viviana Giustini, Cristina Scarpazza, Marco Rovaris, Valentina Torri Clerici, Diana Ferraro, Simonetta Galgani, Claudio Solaro, Marta Zaffira Conti, Andrea Visconti and Luisa Imberti


Cell-Mediated Response to Tumors

Cell-mediated immune responses can be directed against cancer cells, many of which do not have the normal complement of self-proteins, making them a target for elimination. Abnormal cancer cells may also present tumor antigens. These tumor antigens are not a part of the screening process used to eliminate lymphocytes during development thus, even though they are self-antigens, they can stimulate and drive adaptive immune responses against abnormal cells.

Presentation of tumor antigens can stimulate naïve helper T cells to become activated by cytokines such as IL-12 and differentiate into TH1 cells. TH1 cells release cytokines that can activate natural killer (NK) cells and enhance the killing of activated cytotoxic T cells. Both NK cells and cytotoxic T cells can recognize and target cancer cells, and induce apoptosis through the action of perforins and granzymes. In addition, activated cytotoxic T cells can bind to cell-surface proteins on abnormal cells and induce apoptosis by a second killing mechanism called the CD95 (Fas) cytotoxic pathway.

Despite these mechanisms for removing cancerous cells from the body, cancer remains a common cause of death. Unfortunately, malignant tumors tend to actively suppress the immune response in various ways. In some cancers, the immune cells themselves are cancerous. In leukemia, lymphocytes that would normally facilitate the immune response become abnormal. In other cancers, the cancerous cells can become resistant to induction of apoptosis. This may occur through the expression of membrane proteins that shut off cytotoxic T cells or that induce regulatory T cells that can shut down immune responses.

The mechanisms by which cancer cells alter immune responses are still not yet fully understood, and this is a very active area of research. As scientists’ understanding of adaptive immunity improves, cancer therapies that harness the body’s immune defenses may someday be more successful in treating and eliminating cancer.

Think About It

  • How do cancer cells suppress the immune system?
  • Describe how the immune system recognizes and destroys cancer cells.

Yale Center for Immuno-Oncology

Professor of Dermatology, Pathology, and Immunobiology Co-Leader, Genetics, Genomics and Epigenetics, Yale Cancer Center Interim Director, Yale Center for Immuno-Oncology Director, Yale SPORE in Skin Cancer

  • Cell Biology
  • Dermatology
  • Melanoma
  • Neoplasm Metastasis
  • Pathology

Professor Emeritus of Immunobiology Member of HTI and VBT

Professor of Medicine (Medical Oncology) Interim Associate Cancer Center Director, Diversity, Equity, and Inclusion Disease Aligned Research Team Leader, Head and Neck Cancers Program Co-Leader, Developmental Therapeutics, Yale Cancer Center

  • Drug Therapy
  • Head and Neck Neoplasms
  • Medical Oncology
  • Chemicals and Drugs
  • Analytical, Diagnostic and Therapeutic Techniques and Equipment
  • Alzheimer Disease
  • Chemistry, Pharmaceutical
  • Pharmacokinetics
  • Pharmacology
  • Biomarkers
  • Neurodegenerative Diseases
  • Positron-Emission Tomography
  • Drug Discovery
  • Drug Development
  • Biomedical Engineering
  • Cell Transformation, Neoplastic
  • Genetics
  • Immunity
  • Immunotherapy
  • Lymphocytes
  • Neoplasm Metastasis
  • Stem Cells
  • Therapeutics
  • Immunotherapy, Adoptive
  • Genomics
  • Systems Biology
  • Metabolomics
  • Bioengineering
  • Synthetic Biology
  • CRISPR-Cas Systems

Paul B. Beeson Professor of Medicine (Rheumatology) and Professor of Immunobiology Paul B. Beeson Professor of Medicine Program Director, Investigative Medicine

  • Antigens, Differentiation, T-Lymphocyte
  • Autoimmune Diseases
  • Biology
  • Immunity
  • Lupus Erythematosus, Systemic
  • Investigative Techniques
  • Rheumatology
  • Cytokines

Assistant Professor Assistant Professor of Medicine (Hematology), Internal Medicine

  • Blood Transfusion
  • Bone Marrow Diseases
  • Immunotherapy
  • Leukemia
  • Lymphoma
  • Multiple Myeloma
  • Hematopoietic Stem Cell Transplantation

William S. and Lois Stiles Edgerly Professor of Neurology and Professor of Immunobiology Chair, Department of Neurology Neurologist-in-Chief, Yale New Haven Hospital

  • Brain Neoplasms
  • Multiple Sclerosis
  • Neurology
  • Neurosciences
  • Autoimmunity

Senior Research Scientist in Dermatology

  • Dermatology
  • Melanocytes
  • Melanoma
  • Signal Transduction
  • Gene Expression
  • Cell Proliferation

Professor of Laboratory Medicine Medical Director, Apheresis Service, Laboratory Medicine Associate Director, Transfusion Medicine Service

  • Anemia, Sickle Cell
  • Blood Transfusion
  • Hematology
  • Immune Tolerance
  • Plasmapheresis
  • Pregnancy Complications, Hematologic
  • Immunity, Humoral
  • Transfusion Medicine

Ensign Professor of Medicine (Medical Oncology) and Professor of Pharmacology Director, Center for Thoracic Cancers Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital Associate Cancer Center Director, Translational Science

  • Lung Neoplasms
  • Medical Oncology
  • Thoracic Neoplasms
  • Clinical Trials, Phase I as Topic
  • Biomarkers, Pharmacological
  • Precision Medicine

Waldemar Von Zedtwitz Professor of Immunobiology and Molecular, Cellular and Developmental Biology and Professor of Epidemiology (Microbial Diseases) Professor of Molecular Cellular and Developmental Biology Investigator, Howard Hughes Medical Institute


Anti-metastatic immunotherapy based on mucosal administration of flagellin and immunomodulatory P10

Current therapies against malignant melanoma generally fail to increase survival in most patients, and immunotherapy is a promising approach as it could reduce the dosage of toxic therapeutic drugs. In the present study, we show that an immunotherapeutic approach based on the use of the Toll-like receptor (TLR)-5 ligand flagellin (Salmonella Typhimurium FliCi) combined with the major histocompatibility complex class II-restricted P10 peptide, derived from the Paracoccidioides brasiliensis gp43 major surface protein, reduced the number of lung metastasis in a murine melanoma model. Compounds were administered intranasally into C57Bl/6 mice intravenously challenged with syngeneic B16F10-Nex2 melanoma cells, aiming at the local (pulmonary) immune response modulation. Along with a marked reduction in the number of lung nodules, a significant increase in survival was observed. The immunization regimen induced both local and systemic proinflammatory responses. Lung macrophages were polarized towards a M1 phenotype, lymph node cells, and splenocytes secreted higher interleukin-12p40 and interferon (IFN)-γ levels when re-stimulated with tumor antigens. The protective effect of the FliCi+P10 formulation required TLR-5, myeloid differentiation primary response gene 88 and IFN-γ expression, but caspase-1 knockout mice were only partially protected, suggesting that intracellular flagellin receptors are not involved with the anti-tumor effect. The immune therapy resulted in the activation of tumor-specific CD4 + T lymphocytes, which conferred protection to metastatic melanoma growth after adoptive transfer. Taken together, our results report a new immunotherapeutic approach based on TLR-5 activation and IFN-γ production capable to control the metastatic growth of B16F10-Nex2 melanoma, being a promising alternative to be associated with chemotherapeutic drugs for an effective anti-tumor responses.


Results

Generating Nbs that preferentially bind AML cells

To develop a strategy to isolate Nbs that can preferentially bind tumor cells in vitro, as well as enable the CAR T cells to induce tumor regression in vivo, we first isolated tumor-specific antibodies ( Figure 1A ) and then identified the matching antigens by the screening of cell surface protein cDNAs (STAR technology).

Generating Nbs that differentially bind tumor cells and empower CAR T cells to kill the tumor cells. (A) Flowchart of AML-specific CAR-compatible Nbs in vivo screening. A llama was immunized with the AML cell line THP-1. An Nb library was generated from the llama PBMCs by molecular cloning. Two rounds of conventional cell-based phage display were applied, which took the T-acute lymphoblastic leukemia cell line Jurkat and the chronic myelogenous leukemia cell line K562 as negative absorption. Thereafter, 1 round of counter-selection was applied to obtain the nanobodies with high affinity. The resultant THP-1–specific Nbs were inserted into a CAR-expressing lenti-vector to generate the Nb–sub-lib CAR (Nb-CAR) library. Human primary T cells were transduced by the Nb-CAR library and injected into NSG mice with THP-1 or K562 tumors to perform the in vivo selection. Nbs that can redirect T cells to enrich in the tumor were amplified using polymerase chain reaction and sequenced. (B) Ten million THP-1 cells or 5 million K562 cells were transplanted into NSG mice subcutaneously, followed by treatment with UTD T cells or Nb–sub-lib CAR T cells. Two weeks later, Nbs from tumor-infiltrated T cells were isolated and identified using polymerase chain reaction amplification (n = 3). (C) The 5 most frequent Nbs in the THP-1 tumor are shown. The Nb-expressing phage was directly used to test the binding to THP-1 cells, Jurkat cells, or K562 cells using a flow cytometry assay, in which the red line was flow with Nb-expressing phage, and the blue line was isotype control. bp, base pair.

Using the STAR approach, we first immunized a llama with THP-1 cells, an aggressive leukemia cell line harboring the MLL-AF9 fusion protein, and then constructed an Nb-expressing phage-display library consisting of � 9 independent members ( Figure 1A ). 21 The library was used for panning with THP-1 cells in vitro, with negative absorption by Jurkat cells (a human acute T-cell leukemia) to exclude Nbs that recognized T cells and with negative absorption by K562 cells (a human chronic myelogenous leukemia cell line) to stringently select AML-specific Nbs. The resultant phage sublibrary (sub-lib) contained Nbs that preferentially bind the cell surface antigens of THP-1 cells with high affinity.

Identifying Nbs capable of endowing CAR T cells with anti–THP-1 tumor activity in vivo

Not all of the enriched sub-lib Nbs were capable of empowering CAR T lymphocytes with antitumor activities. Cytotoxic T-cell effector functions are triggered by antigen recognition by the T-cell receptor (TCR). Upon antigen binding, TCR activation can induce T-cell proliferation 㸐� fold, achieving clonal selection and expansion. The STAR system takes advantage of the T-cell activation system to amplify and enrich tumor-preferred CAR T cells in vivo. To identify CAR-compatible Nbs, we cloned Nbs from the phage sub-lib into a CAR construct to generate Nb-CAR T cells via lentiviral transduction, followed by CAR T-cell treatment in vivo ( Figure 1B ). Fourteen days after T-cell infusion, all tumor tissues were collected, and Nb sequences were decoded from the tumor-infiltrated Nb-CAR T cells. Polymerase chain reaction results indicated that Nb sequences were specifically retrieved from the Nb–sub-lib CAR T-cell–treated THP-1 tumor ( Figure 1B , lane 2) but not from K562- or UTD-treated THP-1 tumor ( Figure 1B ). Among the 5 most enriched unique Nbs, Nb157, Nb163, Nb176, and Nb393 specifically bound THP-1 cells but not Jurkat or K562 cells ( Figure 1C ). Moreover, Nb157 and Nb163 also bound other AML cell lines, such as HL60, NB4, and U937 (supplemental Figure 1, available on the Blood Web site). Together, these results indicated that the STAR system is capable of enriching and isolating multiple Nbs that specifically bound AML cells.

STAR-isolated Nbs redirect CAR T cells to potently kill AML cells in vitro

To test whether STAR-isolated Nbs can guide CAR T cells to kill target tumor cells, these Nb CARs were transduced into activated primary human T cells ( Figure 2A supplemental Figure 2A-B). In the cytotoxicity assay, UTD T cells did not cause obvious cytotoxicity ( Figure 2B-D ) however, Nb157 CAR T cells potently and specifically killed THP-1 cells but not as many of the K562 or Jurkat cells ( Figure 2B,D ). Similarly, Nb163, Nb176, and Nb393 CAR T cells also specifically killed THP-1 cells ( Figure 2C supplemental Figure 3A-B). Nb157 CAR T cells also killed HL60 cells, another human AML cell line ( Figure 2D ). 22

All Nbs isolated by the STAR system empower CAR T cells to potently kill AML cells in vitro. (A) Schematic diagram of Nb CAR structure, including signal peptide (SP), IgG4 mutant (IgG4m) hinge, CD8 transmembrane domain (TM), 4-1BB, and CD3z domain. (B-D) Nb CAR T cells showed potent and specific cytotoxicity against THP-1 or HL60 cells, but not K562 or Jurkat cells, in a dose-dependent manner. UTD T cells did not exert obvious killing (n = 3). THP-1 cells stimulated Nb157 or Nb163 CAR T cells, but not UTD T cells, to release cytokines, including IFN-γ (E) and TNF-α (F) (n = 3). (G) Only THP-1 cells induced Nb157 or Nb163 CAR T cells to degranulate (ie, CD107a localization to the cell membrane) after a 4-hour coculture (n = 3). CellTrace Far Red–labeled Nb157 (H-I) or Nb163 (J-K) CAR T cells were coincubated with heat-inactivated THP-1 cells (I-K) or K562 cells (H-J) for 4 days, followed by flow cytometry analysis. CAR T cells were gated on GFP + signals (n = 3). ***P < .001, 1-way analysis of variance. ns, not significant (P > .05).

We also found that THP-1 cells, but not K562 cells, specifically stimulated Nb157 and Nb163 CAR T cells to release cytokines, including tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) ( Figure 2E-F ). A similar increase in cytokine release was detected with the coincubation of HL60 cells and Nb157 CAR T cells (supplemental Figure 3C). Moreover, THP-1 cells specifically induced CAR T-cell degranulation, as reflected by an increase in cell surface CD107a ( Figure 2G ), and specifically induced proliferation of Nb157 and Nb163 CAR T cells ( Figure 2H-K ). Together, these findings demonstrated that Nb157 and Nb163 CAR T cells were specifically activated by AML cells, leading to enhanced proliferation, cytokine release, and degranulation to kill the AML cells.

Nb CAR T cells potently induce AML tumor regression in vivo

To determine whether Nb CAR T cells suppressed AML tumors in vivo, THP-1 cells were subcutaneously transplanted into NSG mice, followed by treatment with Nb157 CAR T cells, Nb163 CAR T cells, or UTD T cells. The tumors from UTD T cell–treated mice grew exponentially ( Figure 3A-B ). Notably, the tumors in Nb157 or Nb163 CAR T cell–treated mice failed to grow substantially and eventually regressed ( Figure 3A-B ). Histological studies indicated that, although tumors in the UTD T-cell–treated group contained abundant tumor cells ( Figure 3C UTD), the Nb CAR T cells eradicated the cancer cells, leaving fibrotic tissues at the tumor site ( Figure 3C ). Nb157 CAR T cells also demonstrated significant antitumor efficacy against HL60 tumors in vivo ( Figure 3D ). Nb157 and Nb163 CAR T cells failed to induce regression of the nontarget K562 tumors ( Figure 3E supplemental Figure 3D-E), supporting the specificity of CAR T cells’ anti-AML efficacy. Furthermore, a low dose of Nb157 or Nb163 CAR T cells (1.5 million cells per mouse) led to complete remission of the THP-1 tumor, without recurrence, throughout a prolonged maintenance period of 52 days ( Figure 3F ), indicating the ability of Nb CAR T cells to eradicate the tumors in mice.

Nb-redirected CAR T cells potently eradicate AML tumor in vivo. (A-B) Ten million THP-1 cells were transplanted into NSG mice subcutaneously. The tumor reached 150 mm 3 after � days. Three million Nb157 T cells, Nb163 CAR T cells, or UTD T cells were injected IV into the mice separately (n = 4). Tumor engraftment was monitored every other day. Scale bar, 10 mm. (C) Hematoxylin and eosin–stained THP-1 xenografts after treatment with UTD T cells, Nb163 CAR T cells, or Nb157 CAR T cells. Scale bars, 100 μm. (D) Three million Nb157 CAR T cells or UTD T cells were injected IV separately into NSG mice bearing HL60 tumors. Tumor engraftment was monitored every other day (n = 4). (E) Five million K562 cells were transplanted into NSG mice subcutaneously. The tumor reached 150 mm 3 after � days. Three million Nb157 CAR T cells, Nb163 CAR T cells, or UTD T cells were injected into NSG mice separately. Tumor engraftment was monitored every other day (n = 4). (F) A total of 1.5 million Nb157 CAR T cells, Nb163 CAR T cells, or UTD T cells was injected IV separately into NSG mice bearing THP-1 tumor. Tumor engraftment was monitored every other day until the tumors were gone completely (n = 4). ***P < .001, 1-way analysis of variant. ns, not significant.

Moreover, other STAR-isolated Nbs (Nb173 and Nb393) also endowed CAR T cells with anti-AML activity in vivo (supplemental Figure 3F-G), which was confirmed by histological studies (supplemental Figure 3H). Collectively, these results demonstrate that all 4 of the STAR-isolated Nbs were capable of empowering cognate CAR T cells to potently kill AML cells, highlighting an effective approach to isolate CAR-compatible antibodies for developing novel CAR T-cell therapy.

Identification of CD13 as a CAR T-cell target to kill AML cells

To identify the antigens of the isolated Nbs, � human membrane protein cDNAs were individually overexpressed in HEK293T cells and screened by flow cytometry ( Figure 4A ). Nb157 and Nb163 bound the cells transfected with human aminopeptidase N (CD13) ( Figure 4B ). 23 CD13 cDNA expression was also confirmed by western blot ( Figure 4C ). CD13 is preferentially expressed in acute myeloid blast cells. 24 To further confirm that Nb157 or Nb163 CAR T cells killed AML cells by targeting CD13, 3 CD13-knockout THP-1 cell lines were constructed using a guide RNA (gRNA)/Cas9 system, followed by verification via western blot ( Figure 4D ). Consistently, flow cytometry analysis showed that CD13 knockout abrogated the binding of Nb157 and Nb163 ( Figure 4E ) and abolished the killing of target cells by Nb157 CAR T cells ( Figure 4F ). CD13 knockout also diminished the killing of the targets by Nb163 CAR T cells significantly, but not completely, suggesting that possible off-CD13 antigen is recognized by Nb163 ( Figure 4F ). Together, these results demonstrate that Nb157 CAR T cells potently kill AML cells by specifically targeting CD13.

Identification of CD13 as a target to kill AML cells by CAR T cells. (A) Experimental schema. About 3000 cell membrane protein cDNAs were purified and transfected into HEK293T cells separately, followed by flow analysis with Nbs expressing phage and FITC-labeled secondary antibody against phage M13 protein. (B) Flow analysis of Nbs binding to HEK293T cells with CD13 overexpression. (C) Confirmation of CD13 cDNA expression in HEK293T cells by western blot. (D) Western blot was performed to confirm the gRNA/CRISPR-guided CD13-knockout effect in THP-1 cells. Three independent gRNAs were transduced into THP-1 separately, followed by puromycin selection and single individual clone expansion. (E) Flow analysis of Nb157- or Nb163-binding CD13-knockout THP-1 cells. (F) Cytotoxicity assay of CAR/UTD T cells to wild-type (wt) THP-1 or 2 CD13-knockout THP-1 cell lines (CD13 KO) (n = 4). *P < .05, **P <.01, d***P < .001, Student t test. ns. not significant.

Nb157 CAR T cells eradicate PD AML cells in NSG mouse models

To determine whether Nb CAR T cells can also kill PD AML cells, we found that Nb157 and Nb163 can bind PD AML cells by recognizing CD13 ( Figure 5A-B ). PD AML cells were also potently killed by Nb157 and Nb163 CAR T cells in the in vitro cytotoxicity assays ( Figure 5C-D ). Thereafter, we sought to examine the therapeutic effect of the CAR T cells against PD AML in vivo. To this end, NSG mice were transplanted with PD AML cells, followed by treatment with UTD or Nb157 CAR T cells 2 weeks later. The Kaplan-Maier curve showed that all control mice had died by 45 days after PD AML cell infusion however, Nb157 CAR T-cell infusion significantly prolonged the life of the treated mice to 㺐 days, without obvious toxicity or weight loss ( Figure 5E supplemental Figure 4A).

Nb157 CAR T cells display antitumor activity in patient-derived AML cells in an NSG mouse model. Nb157 (A) and Nb163 (B) recognized PD AML cells by flow analysis. Nb157 (C) and Nb163 (D) CAR T cells specifically killed PD AML cells in vitro in a dose-dependent manner (n = 4). (E) Nb157 CAR T cells efficiently prolonged survival of NSG mice bearing PD AML. In brief, 20 million PD AML cells were injected into NSG mice, followed by treatment with 3 million Nb157 CAR T cells or UTD T cells, and survival of mice was monitored (n = 10, each group). (F-I) PD AML in NSG bone marrow and spleen was monitored after Nb157 CAR T cell treatment by staining with anti-human CD45/CD3/CD33, followed by flow cytometry analysis (n = 3). (J-K) At the end points of each group of experiments, mice spleens were harvested and fixed with paraformaldehyde, followed by immunofluorescence staining of anti-human CD3(red)/CD33(green) and DAPI (blue nuclear).

To investigate the dynamics of CAR T-cell treatment in vivo, we monitored the change in AML and UTD/CAR T cells in the bone marrow, spleen, and peripheral blood. In the first week after T-cell treatment, few CD33 + AML cells, but a large percentage of CD3 + T cells (㺐% of human CD45 + ), were detectable in the bone marrow in both groups ( Figure 5F-G ). Notably, in the second week after T-cell treatment, compared with UTD T cells, Nb157 CAR T cells markedly reduced the accumulation of CD33 + AML cells in bone marrow ( Figure 5H-I ). Consistently, CD33 + AML cells decreased substantially following Nb157 CAR T-cell treatment (supplemental Figure 4B), and more T cells were detected in the peripheral blood (supplemental Figure 4C). However, CAR T cells in peripheral blood decreased by the third week after CAR T-cell infusion (supplemental Figure 4C), likely reflecting tumor regression and a decrease in the antitumor response.

Furthermore, immunofluorescent staining of the mouse spleens revealed a large number of CD33 + AML cells in the UTD group ( Figure 5J ). However, all CD33 + AML cells were eradicated, with a large number of CD3 + T cells in the Nb157 CAR T-cell group ( Figure 5K ). Consistently, flow cytometry also showed enrichments for CAR T cells in the bone marrow and spleen were from 30% (day 0) to 70% (day 14 post T cell infusion) (supplemental Figures 2B and 4D). CD8 + T-cell percentage was also higher in the Nb157 CAR T-cell group (59%) than in the UTD T-cell group (33%) (supplemental Figure 4E). Meanwhile, Nb157 CAR can induce persistent memory T-cell phenotypes, including central memory and effector memory populations (supplemental Figure 4F), which were correlated with complete remissions in CAR T-cell clinical therapy. 25,26 Together, these results indicate that Nb157 CAR T cells effectively eliminate PD AML cells in the bone marrow and spleen of recipient mice and significantly prolong their survival.

Combinatory bispecific and split CAR T cells targeting CD13 and TIM3 redirect T cells to eradicate AML xenografts and AML PDXs in vivo

Because CAR T-cell therapy may cause on-target/off-tumor side effects, 27,28 it is ideal to reduce the toxicity by increasing the specificity with multiple tumor markers. In this regard, novel bispecific CAR T cells were developed to synergistically kill the experimental tumor models by targeting ϡ tumor-associated antigen (TAA). 29,30

One other potential TAA, TIM3, an immune-suppressing receptor, is highly expressed in the majority of human AML LSCs 31,32 but not in HSCs. A combinatory bispecific and split CAR (BissCAR) T-cell system was developed to effectively kill CD13 + TIM3 + LSCs, while maintaining a reduced impact on normal cells that only express CD13 ( Figure 6A ). TIM3 expression was extremely low in normal donor bone marrow but high in the LSC subset (CD34 + CD38 − CD90 − ) ( Figure 6B , upper panels). In contrast, a high percentage of TIM3 and CD13 double-positive cells was detected in the LSC-enriched population (CD34 + CD38 − ) from PD AML cells but not normal donor bone marrow ( Figure 6B ), indicating the high coexpression of CD13 and TIM3 in LSCs, which was consistent with previous reports. 31,32

In vivo, combinatorial bispecific and split CD13 and TIM3 CAR T cells eradicate tumor expressing CD13 and TIM3, but not tumor expressing only CD13. (A) Schematic diagram of combinatorial bispecific and split CD13 and TIM3. Nb157 linked with CD3z recognized CD13 on normal HSCs or LSCs. Anti-TIM3 linked with CD28 and 4-1BB recognized TIM3 only on LSCs. Such Biss CAR T cells can be fully activated only by LSCs but not by HSCs. (B) Flow cytometry showing the expression of TIM3, CD90, CD13 on normal donor bone marrow cells (ND-BM) or PD AML cells, which were gated from CD45 + Lin − CD34 + CD38 − subsets. Ten million NB4 (C) or NB4-TIM3 (D) cells were transplanted subcutaneously into NSG mice to form 100-mm 3 tumors. Three million combinatorial BissCAR T cells, conventional Nb157 CAR T cells, or UTD T cells were injected IV into each NSG mouse with the tumors. The engraftment volume was monitored by measuring the length and width of the tumor every other day (n = 4). (E) Three weeks after mice with NB4 or NB4-TIM3 tumors were treated with BissCAR T cells or UTD T cells, human T-cell (CD3 + ) numbers in mouse peripheral blood were analyzed by flow cytometry and quantified using CountBright counting beads (n = 3). *P < .05, Student t test.

NB4(CD13 + TIM3 − ) and NB4-TIM3(CD13 + TIM3 + ) cell lines were generated to mimic the HSC and LSC models (supplemental Figure 5A-B). Next, a conventional TIM3-BBz CAR was generated (supplemental Figure 5C), which guided the T cells to kill NB4-TIM3 cells potently and specifically in vitro and suppressed NB4-TIM3 tumor growth in vivo (supplemental Figure 5D-E).

We then constructed the BissCAR, in which Nb157 recognizing CD13 was linked to CD3z and anti-TIM3 scFv recognizing TIM3 was linked to CD28 and 4-1BB costimulatory domains ( Figure 6A supplemental Figure 5F). The resulting BissCAR expression on the T cells was verified by flow cytometry (supplemental Figure 5G). An in vitro killing assay showed that BissCAR T cells killed NB4 and NB4-TIM3 cells, because the CD13 recognition elicited CD3z signaling to induce target death in vitro (supplemental Figure 5H). 29 Moreover, compared with NB4 cells, NB4-TIM3 cells increased the secretion of IFN-γ and TNF-α from BissCAR T cells (supplemental Figure 5I-J). The enhanced cytokine secretion was also dependent on NB157-CD3z signaling, because K562-TIM3(CD13 − TIM3 + ) cells failed to induce the BissCAR T cells to release the cytokines (supplemental Figure 5I-J).

In the NB4 xenograft models, BissCAR T cells only moderately suppressed tumor growth compared with complete elimination when using Nb157 CAR T-cell treatment ( Figure 6C ). However, BissCAR T cells could eradicate the NB4-TIM3 tumor as potently as Nb157 CAR T cells ( Figure 6D ). These results indicate that BissCAR T cells are capable of completely shrinking the tumor expressing CD13 and TIM3, but they spared the cells expressing only CD13. Consistently, BissCAR T-cell number in peripheral blood in NB4-TIM3 tumor-bearing mice was significantly higher than in NB4 tumor-bearing mice ( Figure 6E ).

We further explored whether BissCAR T cells can suppress PD AML cells. To this end, PD AML cells were transplanted into NSG mice to induce leukemia, followed by treatment with BissCAR or UTD T cells 2 weeks later ( Figure 7A ). The appearance of CD33 + AML cells or CD3 + T cells in peripheral blood was monitored weekly ( Figure 7B-C ). The results indicated that, following the first week of injection, peripheral blood AML cells gradually decreased in the BissCAR T-cell group ( Figure 7B ), consistent with heavy leukemic infiltration in the spleen in the later stage ( Figure 5H supplemental Figure 4B). Notably, treatment with BissCAR T cells, but not with UTD T cells, increased peripheral T-cell number 1 week after the T-cell injection, reflecting the quick activation and proliferation of CAR T cells to kill AML cells ( Figure 7C ). Consistently, BissCAR T-cell treatment significantly prolonged survival of the mice compared with the UTD T-cell group ( Figure 7D ). It has been reported that various immune-suppressing factors weaken the immunotherapy for AML, such as the PD-1, TIM3 immune checkpoint molecules, and regulatory T cells (Tregs). 33 -35 Compared with UTD T cells, BissCAR T cells have lower PD-1 and TIM3 expression in the bone marrow (supplemental Figure 6A-F). BissCAR T cells and UTD T cells have similar low PD-1 and TIM3 expression in the mouse spleen however, the PD-1/TIM3 levels were not correlated with resistance to CAR T cells, because CAR T cells eradicated AML in our xenograft and PDX models. Low percentages of Tregs were consistently detected in the bone marrow and spleen of mice injected with BissCAR T cells or UTD T cells (supplemental Figure 6G-K). We did not observe any T-cell suppression from Tregs, because of the robust elimination of the leukemia. Therefore, the results demonstrate that BissCAR T cells can effectively eradicate the double-positive PD AML cells in this clinically relevant model.

BissCAR T cells targeting CD13 and TIM3 eradicate AML PDXs, but with reduced toxicity to human HSCs in vivo. (A) Schematic diagram of AML PDX mice treated with control or BissCAR T cells. Twenty million PD AML cells were injected into NSG mice, followed by injection of 5 million BissCAR T cells or UTD T cells 2 weeks later. Next, human peripheral blood CD3 + cells were analyzed by serial bleeding weekly. (B-C) PD AML cells or T cells in mouse peripheral blood were monitored weekly by flow staining with anti-human CD33 or anti-human CD3 antibodies. Blood volume was normalized and quantified using CountBright counting beads (n = 3). (D) Mice survival was monitored and recorded (n = 6 per group). (E) Schematic diagram of HIS mice for evaluation of human HSC toxicity. A total of 1.5 million normal donor bone marrow (BM) CD34 + cells was injected into each NSG mouse. Four weeks later, 3 million Nb157 anti-TIM3 BissCAR T cells, conventional Nb157 CAR T cells, or UTD T cells were injected IV, followed by flow cytometry analysis of peripheral blood and bone marrow (n = 5 per group for BissCAR and UTD T cells n = 3 per group for Nb157 T cells). (F) Bone marrow of HIS mice, which were treated with T cells for 3 weeks, was analyzed by flow cytometry after staining with CD45/Lin/CD34/CD38/7-AAD. Representative fluorescence-activate cell sorting plots were used to identify HSC (CD34 + CD38 − ) and myeloid progenitors (CD34 + CD38 + ). (G) HSCs (CD45 + Lin − CD34 + CD38 − ) in the bone marrow of HIS mice were analyzed by flow cytometry 3 weeks after the initial treatment. (H) Myeloid progenitors (CD45 + Lin − CD34 + CD38 − ) in the bone marrow of HIS mice were analyzed by flow cytometry 3 weeks after the initial treatment. (I) Monocytes (human CD45 + CD33 + ) from peripheral blood of HIS mice were analyzed by flow cytometry 3 weeks after the initial treatment cell number and blood volume were quantified using CountBright counting beads. In (G-I), n = 5 per group for BissCAR T cells and UTD T cells, n = 3 per group for Nb157 T cells. *P < .05, **P < .01, ***P < .001, Student t test.

Combinatory BissCAR T cells targeting CD13 and TIM3 have reduced toxicity to HSCs in vivo

We also investigated the impact of BissCAR T cells on normal human HSCs. Humanized immune system (HIS) mice were used to assess hematopoietic toxicity of BissCAR T cells ( Figure 7E ). NSG mice were conditioned with busulfan and engrafted with bone marrow CD34 + cells from a normal adult donor, followed by treatment with BissCAR, Nb157 CAR, or UTD T cells 4 weeks later. Bone marrow from these mice was collected for analysis 3 weeks after treatment. Nb157 CAR T cells almost completely depleted CD34 + CD38 − HSCs, CD34 + CD38 + myeloid progenitors, and peripheral monocytes ( Figure 7F-I ). Notably, BissCAR T cells significantly reduced the toxicity to HSCs, retaining �% of the human HSC-enriched population and the myeloid progenitors of normal control mice ( Figure 7F-H ). Moreover, BissCAR T cells significantly reduced the monocytes in peripheral blood and allowed the protection of part of the monocytes in peripheral blood in BissCAR T-cell–injected mice compared with Nb157 CAR T-cell–injected mice ( Figure 7I ). Together, these results indicate that BissCAR T cells effectively eradicate PD AML cells ( Figure 7B-D ) and have much reduced toxicity to sensitive human HSCs ( Figure 7F-I ), suggesting BissCAR T cells as a valuable approach to treat human AML with reduced and tolerable hematopoietic toxicity.


13.5: Cancer Immunobiology and Immunotherapy - Biology

All articles published by MDPI are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by MDPI, including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited.

Feature Papers represent the most advanced research with significant potential for high impact in the field. Feature Papers are submitted upon individual invitation or recommendation by the scientific editors and undergo peer review prior to publication.

The Feature Paper can be either an original research article, a substantial novel research study that often involves several techniques or approaches, or a comprehensive review paper with concise and precise updates on the latest progress in the field that systematically reviews the most exciting advances in scientific literature. This type of paper provides an outlook on future directions of research or possible applications.

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to authors, or important in this field. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.


13.5: Cancer Immunobiology and Immunotherapy - Biology

Clonally expanded EOMES(+) Tr1-like cells in primary and metastatic tumors are associated with disease progression

(1) Bonnal RJP (2) Rossetti G (3) Lugli E (4) De Simone M (5) Gruarin P (6) Brummelman J (7) Drufuca L (8) Passaro M (9) Bason R (10) Gervasoni F (11) Della Chiara G (12) D'Oria C (13) Martinovic M (14) Curti S (15) Ranzani V (16) Cordiglieri C (17) Alvisi G (18) Mazza EMC (19) Oliveto S (20) Silvestri Y (21) Carelli E (22) Mazzara S (23) Bosotti R (24) Sarnicola ML (25) Godano C (26) Bevilacqua V (27) Lorenzo M (28) Siena S (29) Bonoldi E (30) Sartore-Bianchi A (31) Amatu A (32) Veronesi G (33) Novellis P (34) Alloisio M (35) Giani A (36) Zucchini N (37) Opocher E (38) Ceretti AP (39) Mariani N (40) Biffo S (41) Prati D (42) Bardelli A (43) Geginat J (44) Lanzavecchia A (45) Abrignani S (46) Pagani M

By analyzing CD4 + T cells from CRC and NSCLC primary tumors and metastases, Bonnal et al. showed intratumoral enrichment of clonotypically distinct Foxp3 + Treg cells and Eomes + granzyme K + Foxp3 - type 1 regulatory T (Tr1)-like cells. Both subsets were also shown in melanoma, breast, and liver tumors. Tr1-like cells expressed PD-1 and chitinase-3-like protein 2 (CHI3L2) as markers, produced IL-10 and IFNγ, suppressed CD4 + and CD8 + T cell proliferation comparably to Foxp3 + Tregs, and were increased in more advanced disease. High CHI3L2 expression correlated with good response to anti-PD-1/PD-L1 therapy in patients with melanoma.

Contributed by Paula Hochman

(1) Bonnal RJP (2) Rossetti G (3) Lugli E (4) De Simone M (5) Gruarin P (6) Brummelman J (7) Drufuca L (8) Passaro M (9) Bason R (10) Gervasoni F (11) Della Chiara G (12) D'Oria C (13) Martinovic M (14) Curti S (15) Ranzani V (16) Cordiglieri C (17) Alvisi G (18) Mazza EMC (19) Oliveto S (20) Silvestri Y (21) Carelli E (22) Mazzara S (23) Bosotti R (24) Sarnicola ML (25) Godano C (26) Bevilacqua V (27) Lorenzo M (28) Siena S (29) Bonoldi E (30) Sartore-Bianchi A (31) Amatu A (32) Veronesi G (33) Novellis P (34) Alloisio M (35) Giani A (36) Zucchini N (37) Opocher E (38) Ceretti AP (39) Mariani N (40) Biffo S (41) Prati D (42) Bardelli A (43) Geginat J (44) Lanzavecchia A (45) Abrignani S (46) Pagani M

By analyzing CD4 + T cells from CRC and NSCLC primary tumors and metastases, Bonnal et al. showed intratumoral enrichment of clonotypically distinct Foxp3 + Treg cells and Eomes + granzyme K + Foxp3 - type 1 regulatory T (Tr1)-like cells. Both subsets were also shown in melanoma, breast, and liver tumors. Tr1-like cells expressed PD-1 and chitinase-3-like protein 2 (CHI3L2) as markers, produced IL-10 and IFNγ, suppressed CD4 + and CD8 + T cell proliferation comparably to Foxp3 + Tregs, and were increased in more advanced disease. High CHI3L2 expression correlated with good response to anti-PD-1/PD-L1 therapy in patients with melanoma.

Contributed by Paula Hochman

ABSTRACT: Regulatory T (T(reg)) cells are a barrier for tumor immunity and a target for immunotherapy. Using single-cell transcriptomics, we found that CD4(+) T cells infiltrating primary and metastatic colorectal cancer and non-small-cell lung cancer are highly enriched for two subsets of comparable size and suppressor function comprising forkhead box protein P3(+) T(reg) and eomesodermin homolog (EOMES)(+) type 1 regulatory T (Tr1)-like cells also expressing granzyme K and chitinase-3-like protein 2. EOMES(+) Tr1-like cells, but not T(reg) cells, were clonally related to effector T cells and were clonally expanded in primary and metastatic tumors, which is consistent with their proliferation and differentiation in situ. Using chitinase-3-like protein 2 as a subset signature, we found that the EOMES(+) Tr1-like subset correlates with disease progression but is also associated with response to programmed cell death protein 1-targeted immunotherapy. Collectively, these findings highlight the heterogeneity of T(reg) cells that accumulate in primary tumors and metastases and identify a new prospective target for cancer immunotherapy.

Author Info: (1) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (2) Istituto Nazionale Genetica Mole

Author Info: (1) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (2) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (3) Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. Flow Cytometry Core, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. (4) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. Department of Radiation Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (5) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (6) Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. (7) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (8) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (9) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (10) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (11) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (12) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. (13) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (14) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (15) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (16) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (17) Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. (18) Laboratory of Translational Immunology, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. (19) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (20) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (21) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (22) Division of Hematopathology, European Institute of Oncology (IEO) IRCCS, Milan, Italy. (23) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (24) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (25) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (26) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (27) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. (28) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. Department of Oncology and Hemato-Oncology, Universit degli Studi di Milano, Milan, Italy. (29) Pathology and Cytogenetics Unit, Grande Ospedale Metropolitano Niguarda, Milan, Italy. (30) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. Department of Oncology and Hemato-Oncology, Universit degli Studi di Milano, Milan, Italy. (31) Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy. (32) Faculty of Medicine and Surgery Vita-Salute San Raffaele University, Milan, Italy. Division of Thoracic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy. (33) Division of Thoracic Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy. (34) Division of Thoracic Surgery, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy. Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy. (35) Department of Surgery, Milano-Bicocca University, San Gerardo Hospital, Monza, Italy. (36) Department of Pathology, San Gerardo Hospital, Monza, Italy. (37) Unit Operativa Chirurgia Epatobiliopancreatica e Digestiva, Ospedale San Paolo, Milan, Italy. Department of Health Sciences, Universit degli Studi di Milano, Milan, Italy. (38) Unit Operativa Chirurgia Epatobiliopancreatica e Digestiva, Ospedale San Paolo, Milan, Italy. (39) Unit Operativa Chirurgia Epatobiliopancreatica e Digestiva, Ospedale San Paolo, Milan, Italy. (40) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. Department of Biosciences, University of Milan, Milan, Italy. (41) Department of Transfusion Medicine and Hematology, IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. (42) Candiolo Cancer Institute, Fondazione del Piemonte per l'Oncologia-IRCCS, Turin, Italy. Department of Oncology, University of Torino, Turin, Italy. (43) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. [email protected] Department of Clinical Sciences and Community Health, Universit degli Studi, Milan, Italy. [email protected] (44) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. [email protected] (45) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. [email protected] Department of Clinical Sciences and Community Health, Universit degli Studi, Milan, Italy. [email protected] (46) Istituto Nazionale Genetica Molecolare Romeo ed Enrica Invernizzi, Milan, Italy. [email protected] FIRC Institute of Molecular Oncology (IFOM), Milan, Italy. [email protected] Department of Medical Biotechnology and Translational Medicine, Universit degli Studi, Milan, Italy. [email protected]


Watch the video: Νέος τρόπος αντιμετώπισης του καρκίνου με ανοσοθεραπεία (August 2022).