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Novel targets for immunotherapy associated with exhausted CD8 + T cells in cancer

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Abstract

In response to prolonged stimulation by tumour antigens, T cells gradually become exhausted. There is growing evidence that exhausted T cells not only lose their potent effector functions but also express multiple inhibitory receptors. Checkpoint blockade (CPB) therapy can improve cancer by reactivating exhausted effector cell function, leading to durable clinical responses, but further improvements are needed given the limited number of patients who benefit from treatment, even with autoimmune complications. Here, we suggest, based on recent advances that tumour antigens are the primary culprits of exhaustion, followed by some immune cells and cytokines that also play an accomplice role in the exhaustion process, and we also propose that chronic stress-induced hypoxia and hormones also play an important role in promoting T-cell exhaustion. Understanding the classification of exhausted CD8+ T-cell subpopulations and their functions is important for the effectiveness of immune checkpoint blockade therapies. We mapped the differentiation of T-cell exhausted subpopulations by changes in transcription factors, indicating that T-cell exhaustion is a dynamic developmental process. Finally, we summarized the novel immune checkpoints associated with depletion in recent years and combined them with bioinformatics to construct a web of exhaustion-related immune checkpoints with the aim of finding novel therapeutic targets associated with T-cell exhaustion in malignant tumours, aiming to revive the killing ability of exhausted T cells and restore anti-tumour immunity through combined targeted immunotherapy.

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The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author/s.

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Funding

This work was supported by the joint project of Sichuan University andLuzhou Municipal Government (2020CDLZ-24); The project of Science and Technology Department of Sichuan Province (2022NSFSC0699); the Open Programme of Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province (HYX21005); the project of Southwest Medical University (2021ZKQN016).

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Authors and Affiliations

  1. Public Center of Experimental Technology, The School of Basic Medical Sciences, Southwest Medical University, No 1, Xianglin road, Luzhou City, 646000, Sichuan Province, China

    Lulu Zhang, Bo Zhang, Lin Li, Yingchun Ye, Yuchuan Wu, Qing Yuan, Wenfeng Xu, Xue Wen, Xiyuan Guo & Siji Nian

  2. Department of Laboratory Medicine, The Affiliated Hospital of Southwest Medical University, Sichuan, 646000, People’s Republic of China

    Wenfeng Xu

  3. Division of Clinical Chemistry, Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand

    Xiyuan Guo

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  1. Lulu Zhang
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  2. Bo Zhang
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  3. Lin Li
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  4. Yingchun Ye
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  5. Yuchuan Wu
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  6. Qing Yuan
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  7. Wenfeng Xu
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  8. Xue Wen
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  9. Xiyuan Guo
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  10. Siji Nian
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Contributions

LZ: Resources; Software; Writing – original draft. BZ: Resources; Writing – original draft. LL: Software. YY: Resources; Writing – original draft. YW: Resources; Software. QY: Software; Supervision. WX, XW: Resources; Software. XW: Resources; Software. XG: Supervision. SN: Supervision. All authors reviewed the manuscript.

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Correspondence to Xiyuan Guo or Siji Nian.

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Zhang, L., Zhang, B., Li, L. et al. Novel targets for immunotherapy associated with exhausted CD8 + T cells in cancer. J Cancer Res Clin Oncol 149, 2243–2258 (2023). https://doi.org/10.1007/s00432-022-04326-1

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