Abstract 4240: Tumor PD-L1 induction associated with dietary protein restriction is modulated by PERK activation

Abstract

Abstract Tumor cells rely on the Integrated Stress Response (ISR) to adapt to different environmental and physiological stresses. The ISR is comprised of four eIF2 kinases that sense different stresses and catalyze phosphorylation of the alpha subunit of eIF2. This results in inhibition of global translation initiation, but at the same time results in preferential translation of select mRNA transcripts in order to relieve stress. Recent work has suggested that programmed death-ligand 1 (PD-L1), a cell surface protein commonly upregulated by tumors to evade the immune system, may be translationally regulated by the ISR in cancer. PD-L1 interaction with immune-checkpoint receptor programmed death-1 (PD-1) leads to the negative regulation of T cell activation and inhibitors that block the PD-L1/PD-1 interaction are widely used to treat different cancers. The ISR may serve as a novel therapeutic target to modulate PD-L1 protein levels and treat immune-evasive cancers. Our group has previously reported that dietary protein restriction increases the anti-tumor effect of PD-1 inhibition in the RENCA kidney cancer mouse model. Here, we show that in the RENCA model, phospho-PERK and phospho-eIF2α protein levels correlate with PD-L1 induction associated with dietary protein restriction. This is supported by TCGA data that shows a correlation between PERK and PD-L1 mRNA levels in different genitourinary cancers. In vitro, activation of the eIF2 kinases PERK and GCN2 by ER stress and amino acid starvation, respectively, in both RENCA cells and prostate cancer cells, leads to induction of PD-L1 protein without changing mRNA levels, suggesting preferential translation under stress conditions. Inhibiting PERK using selective inhibitors blocked ER stress-induced induction of PD-L1. These data support the notion that PD-L1 is induced by dietary protein restriction and is translationally regulated by the ISR. Modulating PD-L1 protein levels in immune-evasive tumors by targeting the ISR in the context of dietary protein restriction may enhance the anti-tumor response to immune checkpoint inhibitors. Citation Format: Ricardo Cordova, Sean Colligan, Chris Rupert, Ronald Wek, Kirk Staschke, Roberto Pili. Tumor PD-L1 induction associated with dietary protein restriction is modulated by PERK activation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4240.