Hypoxia-Induced Changes in Effector T Cells Are Linked to Poor Outcomes in Melanoma 2322

Description Our study highlights hypoxia’s impact on T cell localization and function in melanoma, emphasizing the importance of TME oxygenation in immunotherapy. Through mathematical modeling of melanoma tissue microarrays, we mapped CD4 and CD8 T cell distributions relative to blood vessels and oxygen levels. T cells preferentially accumulated in oxygen-rich areas near vessels, while hypoxic regions were largely T cell-depleted, suggesting oxygen as a critical factor influencing T cell infiltration patterns within tumors. To assess functional impacts, we cultured effector T cells under hypoxic and normoxic conditions. Hypoxia significantly reduced T cell functionality and induced a unique gene signature associated with resting, non-activated states, which correlated with lower OS and PFS in melanoma patients, especially among non-responders to immune checkpoint inhibitor therapy. This suggests that hypoxia-related changes in T cells may contribute to poor clinical outcomes. Finally, comparison of the hypoxia-induced gene signature with a single-cell atlas of tumor-infiltrating lymphocytes revealed alignment with a stress-response state in T cells, indicating that hypoxia drives T cells toward a stress-response state that impairs their functional capacity in the TME. These findings underscore hypoxia as a barrier to effective T cell infiltration and activation in melanoma, suggesting TME oxygenation as a critical target to enhance immunotherapy outcomes. Funding Sources This research was funded the NIH/NCI grants R01CA250514, and the VoLo Health Foundation.