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MHC class I-independent activation of virtual memory CD8 T cells induced by chemotherapeutic agent-treated cancer cells

Cellular & Molecular Immunology volume 18, pages 723–734 (2021)Cite this article

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Abstract

Cancer cells can evade immune recognition by losing major histocompatibility complex (MHC) class I. Hence, MHC class I-negative cancers represent the most challenging cancers to treat. Chemotherapeutic drugs not only directly kill tumors but also modulate the tumor immune microenvironment. However, it remains unknown whether chemotherapy-treated cancer cells can activate CD8 T cells independent of tumor-derived MHC class I and whether such MHC class I-independent CD8 T-cell activation can be exploited for cancer immunotherapy. Here, we showed that chemotherapy-treated cancer cells directly activated CD8 T cells in an MHC class I-independent manner and that these activated CD8 T cells exhibit virtual memory (VM) phenotypes. Consistently, in vivo chemotherapeutic treatment preferentially increased tumor-infiltrating VM CD8 T cells. Mechanistically, MHC class I-independent activation of CD8 T cells requires cell–cell contact and activation of the PI3K pathway. VM CD8 T cells contribute to a superior therapeutic effect on MHC class I-deficient tumors. Using humanized mouse models or primary human CD8 T cells, we also demonstrated that chemotherapy-treated human lymphomas activated VM CD8 T cells independent of tumor-derived MHC class I. In conclusion, CD8 T cells can be directly activated in an MHC class I-independent manner by chemotherapy-treated cancers, and these activated CD8 T cells may be exploited for developing new strategies to treat MHC class I-deficient cancers.

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Acknowledgements

We thank Dr. Julie Lang and Jeremy Shulman from the TRNPM facility for providing humanized BRGS mice and human peripheral blood samples and Alexandra Krinsky, Nicholas Rotello Kuri, and Kole Degolier for technical help. We apologize to those whose work was not cited due to length restrictions. This work was supported by University of Colorado School of Medicine and Cancer Center startup funds to JHW, Cancer League of Colorado grants R21-CA184707, R21-AI110777, R01-CA166325, R21-AI133110, and R01-CA229174 to J.H.W., and a fund from American Cancer Society (ACS IRG #16–184–56) to Z.C. X.W. was supported by an AAI Careers in Immunology Fellowship. R.A.W. is supported by an NIH F31 fellowship (F31DE027854). S.M.Y.C. is supported by an NIH T32 fellowship (T32 AI007405).

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  1. Department of Immunology and Microbiology, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA

    Xiaoguang Wang, Brittany C. Waschke, Rachel A. Woolaver, Samantha M. Y. Chen, Zhangguo Chen & Jing H. Wang

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  1. Xiaoguang Wang
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Contributions

J.H.W. was responsible for conceptualization, funding acquisition, supervision, project administration, and resources. X.W. and J.H.W. designed the experiments. X.W. performed most of the experiments with the help of B.C.W., R.A.W., S.M.Y.C., and Z.C., who are responsible for the investigation of the study. X.W., R.A.W. and J.H.W. wrote the paper.

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Correspondence to Jing H. Wang.

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Wang, X., Waschke, B.C., Woolaver, R.A. et al. MHC class I-independent activation of virtual memory CD8 T cells induced by chemotherapeutic agent-treated cancer cells. Cell Mol Immunol 18, 723–734 (2021). https://doi.org/10.1038/s41423-020-0463-2

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