Autophagy Induced due to Moderate Endoplasmic Reticulum Stress in T Cells Enhances Immunotherapeutic Tumor Control

Abstract

Abstract A number of external or internal stimuli cause endoplasmic reticulum (ER) stress conditions. In response to ER stress, stressed cells activate well-orchestrated cellular signaling processes to resolve the stress or remove itself by triggering apoptosis. In the tumor microenvironment, induction of sustained ER stress is known to dampen the antitumor activity of T cells. However, how T cells respond to suboptimal ER stimuli is unknown. Using melanoma antigen gp100 reactive T cells, we found that T cells transiently activate protein kinase R-like endoplasmic reticulum kinase (PERK) dependent signaling network to ameliorate low level of ER stress. While transient PERK activation in T cell enhances stemness, promotes mitochondrial biogenesis, increases T cells anti-tumor immunity in B16 melanoma bearing mouse, overexpression of PERK triggers T cell dysfunctionality and death. Mechanistically, we discovered that transient activation of PERK decreases overall protein translation and induces protective autophagy to prevent cell damage. Conversely, knockdown of PERK abrogates autophagy activation, hampers mitochondrial biogenesis in response to suboptimal ER stress, which in turn compromises antitumor function. Furthermore, blocking autophagy in T cells hampers T cell anti-tumor activity. Lastly, using gp100 reactive LC3-GFP expressing T cells we demonstrated that, T cells that initiate autophagy due to suboptimal ER stress show better anti-tumor potential compared to those, that fail to enter into the process. Overall, these preclinical data highlight that, both transient ER stress and autophagy pathways are important for healthy T cell function and therapeutically, can be manipulated to regulate their antitumor potential.