ATF4 As A Driver of T Cell Inefficacy in Tumors

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PROJECT SUMMARY Programmed cell death protein 1 (PD-1+) tumor infiltrating T cells (TILs) are a subset of T cells in tumors enriched for tumor antigen specificity, and a-PD1 immunotherapy aims to reinvigorate PD-1+ TILs to act against solid tumors. However, PD-1high CD8+ TILs are characterized by terminal exhaustion and poor bioenergetics marked by depolarized mitochondria; therefore, only ~20% of cancer patients across tumor types respond to a-PD-1 therapy, limiting ubiquitous FDA approvals. Multiple stressors such as persistent antigen, hypoxia, and nutrient stress converge to drive CD8+ TIL terminal exhaustion. Thus, identification of a common pathway that programs the response to multiple forms of T cell stress could provide a potent target to reverse TME-mediated dysfunction of the tumor-antigen specific population. Our group demonstrated that CD8+ TILs experience persistent stress through chronic activation of the endoplasmic reticulum (ER) stress sensor PKR ER-like kinase (PERK). PERK signaling drove CD8+ TIL activation and metabolic exhaustion in mouse and human PD-1high CD8+ TILs, and inhibition of PERK induced complete and long-term responses to a-PD-1 therapy in sarcoma bearing mice. New PERK inhibitors that bypass pancreatic toxicity are in development, but first-generation PERK inhibitors induce toxicity in animals due to loss of the acute response. The long-term goal of the parent research program is to identify new molecular targets in the chronic PERK axis that signal cell stress in CD8+ TILs in solid tumors, limiting response to a-PD-1 immunotherapy in sarcoma patients. The goal of the supplemental project is to expand preliminary data that identify that chronic PERK target activating transcription factor 4 (ATF4) instigates cell stress and dysfunction in PD-1high CD8+ TILs. The supplemental project will test the central hypothesis that ATF4 promotes aberrant activation and exhaustion in CD8+ TILs to undermine T cell function in multiple tumor types, limiting response to a-PD-1 immunotherapy. This project directly aligns with the career development goals of the candidate, Coral del Mar Alicea Pauneto, who aims to gain expertise in immune oncology in her graduate work to achieve her long-term goal of enhancing access to cutting-edge tumor immunotherapies for underrepresented minority populations.