Abstract 613: T cell antitumor function requires potassium transport

Abstract

Abstract Background: The past 20 years of translational oncology provide a framework in which the ability to eradicate cancer has increased in direct relation to our understanding of T cell biology. The cancer-killing functions of T cells are often compromised within tumors, allowing disease progression. Tumor-derived factors and the hostile microenvironment contribute to constraining of T cell effector functions and driving terminal differentiation. We previously identified that elevated extracellular K+ characteristics of the tumor microenvironment limits both TCR dependent activation and effector functions, while preserving coincidently preserving T cell stemness (Eil R, Nature 2016 & Science 2019). Despite these findings and the centrality of ion gradients to cellular physiology broadly, our understanding of T cell K+ transport remains rudimentary and cannot account for the pleiotropic role K+ abundance plays in antitumor immunity. In fact, little is known about what K+ transporters T cell express nor their functional regulation. Findings: Here, we report the canonical Na+-K+-ATPase to be intertwined with T cell metabolic homeostasis, memory formation, and antitumor activity and therefore an appealing avenue for T cell reprogramming. We first performed whole-transcriptomic sequencing of CD8+ memory subsets and found that components of the Na+-K+-ATPase were expressed at robust levels that were notably enriched in naïve and memory cells. Despite partially impairing Ca2+ influx, T cells genetically deficient for the Na+-K+-ATPase exhibited constitutive activity in both TCR and Akt-mTOR associated signaling pathways along with rapid acquisition of co-inhibitory surface receptors, mitotic arrest, and functional exhaustion. Mechanistically, we identified pathologic ROS accumulation as the driver of unregulated signaling and rapid exhaustion. In vivo, T cells lacking deficient in Na+-K+-ATPase activity failed to achieve proliferative burst following pathogen challenge and demonstrated severely compromised antitumor function. Our results support a model in which the Na+- K+- ATPase primarily functions in T cells to maintain ROS metabolism, thereby preventing its pathologic accumulation and preserving T cell stemness and antitumor potential. Conclusion: These results uncover a fundamental yet underappreciated aspect of T cell biology with translational implications for the ongoing development of cancer immunotherapies. Immediate applications include pharmacologic and genetic targeting of ion transporters in the setting of immune checkpoint blockade or T cell transfer therapies (i.e. CAR, TCR, TIL). Citation Format: Camille Collier, Matthew McWhorter, Kelly Wucherer, Chelsea Jenkins, Alexandra Bartlett, Robert Eil. T cell antitumor function requires potassium transport [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 613.