Tumor derived acidity enhances T_reg suppressive functions against anti-tumor T_effs

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B160
Abstract ID: 5593

Presenting Author:
Nikita L Mani , Graduate Student at Northwestern Univ. Feinberg Sch. of Med.

Abstract:

Despite the immense progress immunotherapies have made on treatments of cancers, a significant subset of patients fail to sustain durable clinical response. This underscores a critical need for nuanced understanding of the complex tumor immune landscape to enhance the efficacy of therapeutic interventions. Regulatory T cells (Tregs) emerge as pivotal orchestrators of anti-tumor immunity, suppressing effector T cells (Teff). Accumulation of toxic byproducts in the tumor microenvironment (TME), resulting from dysregulated tumor metabolism, and depletion of necessary resources further dampens the effector response. Interestingly, Tregs exhibit resilience to the harsh effects of the TME. Here, we show that acidity, a hallmark of the TME associated with enhanced glycolysis, independently enhances Treg functions. Surprisingly, Tregs exposed to acidity display heightened suppressive functions in vitro compared to those exposed to physiologically neutral pH. Metabolic analyses showed that Tregs adapt to acidity by altering one-carbon folate metabolism, leading to increased oxidative phosphorylation, which promotes enhanced suppression. We show treatment with Na-formate diminishes acidity-experienced activity of Tregs in the TME, rescuing functions of Teffs and limiting tumor growth. Our findings illuminate novel metabolic and cellular adaptations of Tregs in acidic TMEs, providing valuable insights into anti-tumor immunity and offering potential avenues for improving immunotherapies.