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Reversing the mitochondrial stress-induced exhaustion of CD8+ T cells for improving cancer immunotherapy

Cellular & Molecular Immunology volume 18, pages 1634–1637 (2021)Cite this article

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Antigen-specific CD8+ T cells that infiltrate tumor tissue have been considered the primary cytotoxic lymphocytes that exert antitumor effects, building a foundation for current immunotherapies against cancer. However, in the face of continuous antigenic stimulation during chronic infections and cancer, T-cell differentiation leads to a state of incapacitation called T-cell exhaustion, which is a critical barrier to successful T-cell immunotherapy of cancer. The explosive growth of malignant tumor cells accompanied by a dysfunctional vascular system and metabolite competition leads to a stressful tumor microenvironment characterized by low-oxygen tension, acidic interstitial pH, and insufficient nutrients. The evidence for the contribution of the tumor microenvironment to the metabolic reprogramming of exhausted CD8+ T cells has been increasing, but the response of intratumoral T cells to metabolic stress signals is still not fully understood. Findings of a study by Scharping et al.,1 together with other recent evidence, have highlighted that the tumor microenvironment can influence the mitochondrial stress of T cells and drive the trajectory of T-cell differentiation toward exhaustion. These findings add new perspectives on and insights into the molecular initiators of T-cell exhaustion and the combination of strategies that should be utilized to improve the efficacy of immunotherapy, and these perspectives are discussed in this review.

CD8+ T cells, central components of adaptive immunity, are considered as the most powerful soldiers for fighting against intracellular pathogens and tumors. Upon T-cell receptor (TCR) stimulation, naive CD8+ T cells recognize antigenic peptides and then undergo robust activation and differentiate into antigen-specific effector CD8+ T cells. The majority of activated T cells die following antigen clearance and resolution of inflammation, while a small subset is converted to a memory T-cell subpopulation. Memory T cells navigate and are distributed over the whole body and induce rapid cytotoxicity in response to a second encounter with the stimulating antigen. However, during chronic infections and cancer, activated CD8+ T cells are exposed to persistent antigens and/or inflammatory signals and gradually enter a state of exhaustion, resulting in limited control of infections and tumors. Exhausted T cells usually manifest several dysfunctional characteristics with stepwise and progressive loss of effector functions and proliferative capacity, overexpression of multiple inhibitory receptors, altered metabolic fitness, and unique transcriptional and epigenetic signatures. Accordingly, a definition of CD8+ T-cell exhaustion has been proposed in many settings; however, the induction of T cells with exhaustion-like features in vitro has rarely been accomplished. Identifying the drivers of T-cell exhaustion remains a challenge in efforts to attenuate immune dysfunction. Thus, new culture systems capable of recapitulating pathological conditions, as well as new approaches to quantify metabolic and epigenetic reprogramming outcomes in vivo, are critical for investigating T-cell differentiation and exhaustion in different local microenvironments.

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Acknowledgements

This work is supported by the Key Program of National Natural Science Foundation of China (81730039) and National Natural Science Foundation of China Grants (81701574).

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Authors and Affiliations

  1. National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai, China

    Cheng Qian & Xuetao Cao

  2. Laboratory of Immunity and Inflammation, College of Life Sciences, Nankai University, Tianjin, China

    Xuetao Cao

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  1. Cheng Qian
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Correspondence to Cheng Qian or Xuetao Cao.

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Qian, C., Cao, X. Reversing the mitochondrial stress-induced exhaustion of CD8+ T cells for improving cancer immunotherapy. Cell Mol Immunol 18, 1634–1637 (2021). https://doi.org/10.1038/s41423-021-00709-5

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