Cited by 462Cancer Immunotherapy and BiomarkersT-cell and B-cell ImmunologyImmunotherapy and Immune Responses

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Reversing T-cell Dysfunction and Exhaustion in Cancer

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Zarour, Hassane M.·2016·Clinical Cancer Research

DOI 10.1158/1078-0432.ccr-15-1849PMC PMC4872712

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Abstract

In the context of chronic antigen exposure in chronic viral infections and cancer, T cells become exhausted/dysfunctional. These exhausted T cells exhibit defective proliferative capacities and cytokine production, but are not totally inert and may exert lytic functions. Importantly, exhausted T cells upregulate multiple inhibitory receptors/immune checkpoints that bind to their ligands expressed by tumor cells and antigen-presenting cells in the tumor microenvironment (TME). Immune checkpoint blockades with anti-CTL antigen 4 (CTLA-4) and/or anti-programmed death 1 (PD-1) mAbs successfully reinvigorate tumor-infiltrating T lymphocytes and provide persistent clinical benefits to a large number of patients with advanced cancer. This great and long-awaited success for the immunotherapy of cancer has infused considerable enthusiasm in the field of oncology and fostered the development of combinatorial strategies to target the multiple mechanisms of tumor-induced T-cell dysfunction. Here, we review the critical immunoregulatory mechanisms driving T-cell exhaustion in the TME. We also discuss the development of promising combinatorial immunotherapies to counteract the mechanisms of tumor-induced T-cell dysfunction to improve the clinical efficacy of current immune checkpoint blockades. As our understanding of the mechanisms supporting tumor-induced T-cell dysfunction improves based upon preclinical and clinical studies, we expect that novel combinatorial immunotherapies will emerge to improve the clinical outcome of patients with advanced cancers. Clin Cancer Res; 22(8); 1856–64. ©2016 AACR. See all articles in this CCR Focus section, “Opportunities and Challenges in Cancer Immunotherapy.”

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Authors: Zarour, H. M.
Affiliations: University of Pittsburgh (US)
Corresponding author: Zarour, Hassane M.
ORCID: Zarour, Hassane M.
Venue: Clinical Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2016-04-14
Volume: 22
Issue: 8
Pages: 1856-1864
ISSN: 1078-0432 (ISSN-L)
1557-3265
DOI: 10.1158/1078-0432.ccr-15-1849
PMC: PMC4872712
OpenAlex: W2336635113
Cited by: 462
References: 105
Citations by year: 2026: 29 · 2025: 42 · 2024: 35 · 2023: 55 · 2022: 59 · 2021: 64 · 2020: 53 · 2019: 46 · 2018: 38 · 2017: 25 · 2016: 15
FWCI: 4.16
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Clinical Cancer Research (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: NIH Melanoma Research Alliance, and a Clinical Strategy Team Grant from the Cancer Research Institute (R01CA157467 and P50CA121973)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Keywords: T cell exhaustion, T cell dysfunction, tumor microenvironment, immune checkpoint, CTLA-4, PD-1, immune checkpoint blockade, cancer immunotherapy, combination immunotherapy, inhibitory receptors, chronic viral infection, tumor-infiltrating T cells
MeSH terms: Animals, Antibodies, Monoclonal, Antigen-Presenting Cells, Antineoplastic Agents, Gene Expression Regulation, Humans, Immunologic Factors, Neoplasms, T-Lymphocytes, Signal Transduction, Cytokines, Myeloid Cells, Epigenesis, Genetic, Immunomodulation, Molecular Targeted Therapy, Tumor Microenvironment, CTLA-4 Antigen, Costimulatory and Inhibitory T-Cell Receptors, Programmed Cell Death 1 Receptor

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Reversing T-cell Dysfunction and Exhaustion in Cancer

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