Stress relief for cancer immunotherapy: implications for the ER stress response in tumor immunity
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REVIEW
Stress relief for cancer immunotherapy: implications for the ER stress response in tumor immunity Alex M. Andrews1,2,3 · Megan D. Tennant1,2 · Jessica E. Thaxton1,2,3 Received: 15 August 2020 / Accepted: 11 October 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords ER stress · PERK · T cell · Translation · Metabolism · Cancer immunotherapy · ATF4
PERK is a stress‑sensing kinase with roles in antitumor immunity Mammalian cells regularly encounter exogenous cell stress such as nutrient and amino acid deprivation, hypoxia, and reactive oxygen species (ROS). Such cell stressors lead to a burden of misfolded proteins in the endoplasmic reticulum (ER) lumen that engage ER stress sensors to trigger the integrated stress response (ISR) in an attempt to return the cell to homeostatic conditions [1, 2]. Three stress sensors; inositol-requiring enzyme-1α (IRE1α), activating transcription factor 6 (ATF6), and PKR-like ER kinase (PERK) are activated by the unfolded protein response (UPR) [3–5]. Each of the aforementioned sensors lead to the activation Alex M. Andrews and Megan D. Tennant have contributed equally to this work. * Jessica E. Thaxton [email protected] 1
Department of Orthopedics and Physical Medicine, Medical University of South Carolina, 68 President Street, Charleston, SC 29425, USA
2
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
3
Hollings Cancer Center, Charleston, SC 29425, USA
of the regulatory transcription factors XBP1, ATF6p50, and activating transcription factor 4 (ATF4), respectively [6, 7]. The transcriptional programs induced by ER stress and the UPR lead to increased expression of genes required for protein folding, the inhibition of new protein synthesis through regulated IRE1-dependent mRNA decay (RIDD) and the induction of autophagy programs that help to eliminate unfolded proteins in the ER [8, 9]. A key step in activation of the UPR is the direct inhibition of protein translation following PERK activation. Sensing of a burden
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