TIM-3, a promising target for cancer immunotherapy

He, Yayi; Cao, Jie; Zhao, Chao; Li, Xuefei; Zhou, Caicun; Hirsch, Fred R.

doi:10.2147/OTT.S170385

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TIM-3, a promising target for cancer immunotherapy

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Author(s): Yayi He ¹ , Jie Cao ¹ , Chao Zhao ² , Xuefei Li ² , Caicun Zhou ¹ , Fred R Hirsch ³

Publication date (Electronic): 16 October 2018

Journal: OncoTargets and therapy

Publisher: Dove Medical Press

Keywords: immune checkpoint, clinical trial, cancer immunotherapy, T-cell immunoglobulin and mucin domain-3 (TIM-3)

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Abstract

Patients with malignant tumor treated with immunotherapy have received significant clinical benefits over the years. Immune checkpoint blocking agents, such as anti-cytotoxic T-lymphocyte-associated protein-4 (anti-CTLA-4) and anti-programmed cell death protein-1 (anti-PD-1) monoclonal antibodies, have produced impressive clinical results in different types of cancer. T-cell immunoglobulin and mucin domain-3 (TIM-3), another immune checkpoint, could inhibit cancer immunity. Recent studies have highlighted that TIM-3 has an important role to play in T-cell exhaustion and correlates with the outcome of anti-PD-1 therapy. Targeting TIM-3 might be a promising approach for cancer immunotherapy. Here, we review the role of TIM-3 in cancer and clinical trials with TIM-3 inhibitors.

Most cited references 42

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Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

Shohei Koyama, Esra A Akbay, Yvonne Y. Li … (2016)

Despite compelling antitumour activity of antibodies targeting the programmed death 1 (PD-1): programmed death ligand 1 (PD-L1) immune checkpoint in lung cancer, resistance to these therapies has increasingly been observed. In this study, to elucidate mechanisms of adaptive resistance, we analyse the tumour immune microenvironment in the context of anti-PD-1 therapy in two fully immunocompetent mouse models of lung adenocarcinoma. In tumours progressing following response to anti-PD-1 therapy, we observe upregulation of alternative immune checkpoints, notably T-cell immunoglobulin mucin-3 (TIM-3), in PD-1 antibody bound T cells and demonstrate a survival advantage with addition of a TIM-3 blocking antibody following failure of PD-1 blockade. Two patients who developed adaptive resistance to anti-PD-1 treatment also show a similar TIM-3 upregulation in blocking antibody-bound T cells at treatment failure. These data suggest that upregulation of TIM-3 and other immune checkpoints may be targetable biomarkers associated with adaptive resistance to PD-1 blockade.

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Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.

Laurent Monney, Catherine Sabatos, Jason L Gaglia … (2002)

Activation of naive CD4(+) T-helper cells results in the development of at least two distinct effector populations, Th1 and Th2 cells. Th1 cells produce cytokines (interferon (IFN)-gamma, interleukin (IL)-2, tumour-necrosis factor (TNF)-alpha and lymphotoxin) that are commonly associated with cell-mediated immune responses against intracellular pathogens, delayed-type hypersensitivity reactions, and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines (IL-4, IL-10 and IL-13) that are crucial for control of extracellular helminthic infections and promote atopic and allergic diseases. Although much is known about the functions of these two subsets of T-helper cells, there are few known surface molecules that distinguish between them. We report here the identification and characterization of a transmembrane protein, Tim-3, which contains an immunoglobulin and a mucin-like domain and is expressed on differentiated Th1 cells. In vivo administration of antibody to Tim-3 enhances the clinical and pathological severity of experimental autoimmune encephalomyelitis (EAE), a Th1-dependent autoimmune disease, and increases the number and activation level of macrophages. Tim-3 may have an important role in the induction of autoimmune diseases by regulating macrophage activation and/or function.

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Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1.

Shigeki Chiba, Muhammad Baghdadi, Hisaya Akiba … (2012)

The mechanisms by which tumor microenvironments modulate nucleic acid-mediated innate immunity remain unknown. Here we identify the receptor TIM-3 as key in circumventing the stimulatory effects of nucleic acids in tumor immunity. Tumor-associated dendritic cells (DCs) in mouse tumors and patients with cancer had high expression of TIM-3. DC-derived TIM-3 suppressed innate immune responses through the recognition of nucleic acids by Toll-like receptors and cytosolic sensors via a galectin-9-independent mechanism. In contrast, TIM-3 interacted with the alarmin HMGB1 to interfere with the recruitment of nucleic acids into DC endosomes and attenuated the therapeutic efficacy of DNA vaccination and chemotherapy by diminishing the immunogenicity of nucleic acids released from dying tumor cells. Our findings define a mechanism whereby tumor microenvironments suppress antitumor immunity mediated by nucleic acids.

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Author and article information

Journal

Journal ID (nlm-ta): Onco Targets Ther

Journal ID (iso-abbrev): Onco Targets Ther

Journal ID (publisher-id): OncoTargets and Therapy

Title: OncoTargets and therapy

Publisher: Dove Medical Press

ISSN (Electronic): 1178-6930

Publication date Collection: 2018

Publication date (Electronic): 16 October 2018

Volume: 11

Pages: 7005-7009

Affiliations

[1 ]Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People’s Republic of China, caicunzhoudr@ 123456163.com

[2 ]Department of Lung Cancer and Immunology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, Shanghai 200433, People’s Republic of China

[3 ]Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Author notes

Correspondence: Caicun Zhou, Department of Medical Oncology, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University School of Medicine, No 507 Zhengmin Road, Shanghai 200433, People’s Republic of China, Tel +86 65 115 006 3050, Email caicunzhoudr@ 123456163.com

[*]

These authors contributed equally to this work

Article

Publisher ID: ott-11-7005

DOI: 10.2147/OTT.S170385

PMC ID: 6198883

PubMed ID: 30410357

SO-VID: 4d219102-94d9-40fe-8716-7abd4d7e7bb6

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The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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OncoTargets and Therapy (submit here)

TIM-3, a promising target for cancer immunotherapy

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Abstract

Most cited references 42

Adaptive resistance to therapeutic PD-1 blockade is associated with upregulation of alternative immune checkpoints

Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease.

Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1.

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