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Stress relief for cancer immunotherapy: implications for the ER stress response in tumor immunity

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Abstract

The solid tumor microenvironment is replete with factors that present a stress to infiltrating immune cells. Endoplasmic reticulum (ER) stress sensor PKR-like ER kinase (PERK) is primed to sense and respond to the burden of misfolded proteins in the ER lumen induced by cell stressors. PERK has documented roles as a master regulator of acute and chronic responses to cell stress as well as in the regulation of cell metabolism. Here, we provide an overview of the roles of PERK based on what is known and remains to be tested in immune cells in tumors and impacts on tumor control. PERK is one of several ER kinases able to preferentially induce activating transcription factor 4 (ATF4) as a response to cell stress. ATF4 orchestrates the oxidative stress response and governs amino acid metabolism. We discuss the tested role of ATF4 in tumor immunity and provide insight on the dueling protective and deleterious roles that ATF4 may play in the stress of solid tumors.

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Acknowledgements

This work was supported by Grant funds 1R01CA248359-01 to JET, 1R01CA244361-01A1 JET, T32 CA 193201 to AMA, and T32 DE01755 to MDT. We thank Sage Jadrnicek for figure design and artwork.

Funding

1R01CA248359-01 (JET), 1R01CA244361-01A1 (JET), T32 CA 193201 (AMA), T32 DE01755 (MDT).

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  1. Alex M. Andrews and Megan D. Tennant have contributed equally to this work.

Authors and Affiliations

  1. Department of Orthopedics and Physical Medicine, Medical University of South Carolina, 68 President Street, Charleston, SC, 29425, USA

    Alex M. Andrews, Megan D. Tennant & Jessica E. Thaxton

  2. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA

    Alex M. Andrews, Megan D. Tennant & Jessica E. Thaxton

  3. Hollings Cancer Center, Charleston, SC, 29425, USA

    Alex M. Andrews & Jessica E. Thaxton

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All the authors contributed to the manuscript conception, outline, and overall design. AMA reviewed and wrote the first section. MDT reviewed and wrote the second section; JET revised, edited, and formalized the manuscript. All the authors read and approved the final manuscript and agreed that they are accountable for all the aspects of the work and assure the accuracy and integrity of the work.

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Correspondence to Jessica E. Thaxton.

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Andrews, A.M., Tennant, M.D. & Thaxton, J.E. Stress relief for cancer immunotherapy: implications for the ER stress response in tumor immunity. Cancer Immunol Immunother 70, 1165–1175 (2021). https://doi.org/10.1007/s00262-020-02740-3

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