Tim-3 expression and its role in hepatocellular carcinoma

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Abstract

Hepatocellular carcinoma (HCC) is one of the most common tumors in the world, and its mortality is still on the rise. Limited treatments and low chemotherapy sensitivity of HCC make new therapeutic strategies urgently needed. With the rise of immune checkpoint blockade, anti-CTLA-4 antibodies and anti-PD-1 antibodies have shown therapeutic effects in various tumors. T cell immunoglobulin mucin-3 (Tim-3), a newly discovered immune checkpoint molecule, plays a major role in the development of HCC. Tim-3 can be used to evaluate the prognosis and therapeutic effects in HCC, and Tim-3 intervention has shown anti-tumor effects in preclinical experiments. This review summarizes findings regarding Tim-3 and HCC in recent years and discusses the rationale of Tim-3 as a therapeutic target for HCC.

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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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Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition.

Leonid Cherkassky, Aurore Morello, Jonathan Villena-Vargas … (2016)

Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.

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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

Contributors

Zhi Chen: 86-571-87236579 , zjuchenzhi@zju.edu.cn

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 11 October 2018

Publication date PMC-release: 11 October 2018

Publication date Collection: 2018

Volume: 11

Electronic Location Identifier: 126

Affiliations

ISNI 0000 0004 1759 700X, GRID grid.13402.34, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, , Zhejiang University, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, ; 79# Qingchun Road, 6A-17, Hangzhou, 310003 China

Article

Publisher ID: 667

DOI: 10.1186/s13045-018-0667-4

PMC ID: 6182863

PubMed ID: 30309387

SO-VID: 6aa0e994-9c6e-4493-92fb-cd9eac53b64a

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 28 June 2018

Date accepted : 19 September 2018

Funding

Funded by: State S&T Projects of 13th Five Year

Award ID: 2018ZX10302206

Award ID: 2017ZX10202203-007

Award Recipient : Zhi Chen

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatocellular carcinoma,tim-3,immune checkpoint blockade,immunotherapy

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: hepatocellular carcinoma, tim-3, immune checkpoint blockade, immunotherapy

Tim-3 expression and its role in hepatocellular carcinoma

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Karger: Oncology

Most cited references 64

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

Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition.

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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