Abstract 4156: Differential effects of tumor metabolites on T cell activation and effector function

Abstract Over the past decade, immunotherapies have significantly improved clinical outcomes in cancer patients. The FDA approval of ICB for cancer treatment represents a clinical milestone, however, durable responses are observed in only ∼20-40% of patients. The immunosuppressive nature of the tumor microenvironment (TME) presents a major challenge for effective anti-tumor responses. Tumor cells are highly metabolically active compared to other cells in the TME. Processes such as glycolysis and oxygen consumption (OXPHOS) lead to tumor hypoxia and the accumulation of metabolites in the TME. Metabolites found in the TME play key roles in immunosuppressive pathways including the adenosine-A2A receptor (A2AR) signaling pathway, and the Tryptophan-kynurenine-aryl hydrocarbon receptor (AHR) axis. Here we investigated how these metabolic pathways directly affect activation and effector function of T cells. In addition, we examined whether these pathways overlap functionally. To explore how TME metabolites affect T cell function, naïve mouse T cells were activated in the presence of metabolites including lactic acid (Lac), adenosine (Ado), kynurenine (Kyn). After 72 hours, T cells were analyzed via flow cytometry for proliferation and activation. We found that lactic acid decreased T cell frequencies and proliferation, but increased expression of CD39 and CD73, key enzymes involved in the conversion of ATP to Ado. Intriguingly, the combination of Kyn and Ado uniquely promoted T cell activation, showing markedly elevated expression of classical activation and effector markers such as CD44, CD25, and Granzyme B along with reduced CD39 and CD73 levels. Similar findings were observed in a clonogenic killing assay using tumor-specific T cells co-cultured with metabolites corroborating the functional relevance of our observations. Lactate negatively affected T cell killing function and the combination of Kyn and Ado showed the largest increase in killing efficiency. These findings suggest potential synergy between Kyn and Ado pathways in enhancing T cell function within the TME possibly through complementary pathways that bypass or counteract typical immunosuppressive signals. Further mechanistic investigation could unlock new strategies to overcome TME-induced immunosuppression and enhance existing immune based therapies. Citation Format: Daniel Hua, Sadna Budhu, Anais Assouvie, Svena Verma, Mamadou Bah, Jedd D. Wolchok, Taha Merghoub. Differential effects of tumor metabolites on T cell activation and effector function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4156.