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Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment

Cellular & Molecular Immunology volume 17, pages 27–35 (2020)Cite this article

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Abstract

The failure of a massive influx of tumor-infiltrating T lymphocytes to eradicate tumor cells in the tumor microenvironment is mainly due to the dysfunction of T cells hyporesponsive to tumors. T-cell exhaustion and senescence induced by malignant tumors are two important dysfunctional states that coexist in cancer patients, hindering effective antitumor immunity and immunotherapy and sustaining the suppressive tumor microenvironment. Although exhausted and senescent T cells share a similar dysfunctional role in antitumor immunity, they are distinctly different in terms of generation, development, and metabolic and molecular regulation during tumor progression. Here, we discuss the unique phenotypic and functional characteristics of these two types of dysfunctional T cells and their roles in tumor development and progression. In addition, we further discuss the potential molecular and metabolic signaling pathways responsible for the control of T-cell exhaustion and senescence in the suppressive tumor microenvironment. Understanding these critical and fundamental features should facilitate rethinking the unresponsiveness to current immunotherapies in clinical patients and lead to further development of novel and effective strategies that target different types of dysfunctional T cells to enhance cancer immunotherapy.

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Fig. 1: PD-1 and CTLA4 signaling pathways and metabolic regulations involved in T-cell exhaustion in the tumor microenvironment.
Fig. 2: Molecular pathways involved in T-cell senescence in the tumor microenvironment.

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Acknowledgements

Because of space limitations, we apologize to anyone whose excellent studies have been inadvertently omitted. This work was partially funded by grants from the American Cancer Society (RSG-10-160-01-LIB, to G.P.), Melanoma Research Alliance (to G.P.), and NIH (AI097852, AI094478, and CA184379 to G.P.).

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Authors and Affiliations

  1. Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, Saint Louis University School of Medicine, Saint Louis, MO, 63104, USA

    Yangjing Zhao & Guangyong Peng

  2. Department of Immunology, Key Laboratory of Medical Science and Laboratory Medicine of Jiangsu Province, School of Medicine, Jiangsu University, Zhenjiang, 212013, P. R. China

    Yangjing Zhao & Qixiang Shao

  3. Department of Molecular Microbiology & Immunology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA

    Guangyong Peng

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  1. Yangjing Zhao
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  2. Qixiang Shao
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Correspondence to Guangyong Peng.

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Zhao, Y., Shao, Q. & Peng, G. Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment. Cell Mol Immunol 17, 27–35 (2020). https://doi.org/10.1038/s41423-019-0344-8

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  • DOI: https://doi.org/10.1038/s41423-019-0344-8

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