UNRAVELING THE COMPLEX INTERPLAY BETWEEN HEAT-SHOCK TRANSCRIPTION FACTOR 1 (HSF1) NETWORKS AND T-CELL METABOLIC REPROGRAMMING IN ANTI-TUMOR IMMUNITY
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Abstract
Heat Shock Factor 1 (HSF1) is transcriptionally activated in response to a variety of environmental stressors. Data from our laboratory indicates that genetic inactivation of HSF1 significantly delays tumorigenesis in various tumor models. Increasing evidence supports the paradigm that modulating the metabolic bioenergetics of T cells, i.e., inhibiting glycolytic flux, enhances the formation of efficient anti-tumor CD8+ T cells. Since HSF1 is involved in cellular metabolism, in this study, we explored the strategies to reprogram metabolic pathways used by the immune system to improve anti-tumor immunity. We observed that deletion of HSF1 profoundly affects metabolic reprogramming of naïve CD8+ T cells upon anti-CD3/CD28 stimulation in vitro. Furthermore, HSF1-deficient CD8+ T cells show a reduced oxygen consumption rate upon activation. These effects correspond to delayed T cell receptor (TCR) signaling and slower activation of naïve CD8+ T cells upon stimulation, preventing them from moving towards an early exhaustion stage resulting in improved longevity. Furthermore, we were able to demonstrate that these defects in TCR signaling is attributed to HSF1 deletion-mediated redox imbalance (NAD+/NADH), resulting in the attenuation of mitochondrial function characterized by hampered respiratory complex I activity and limiting ATP production. Supplementation of CD8+ T cells with ATP or NAD rescued the defects observed during CD8+ T cell activation and function caused by HSF1 deletion. Additionally, we detected delayed initiation of MC38 tumors that were implanted in the T-cell specific HSF1-deficient mice compared to wild-type mice. In addition, we confirmed that the delay in tumorigenesis observed in T-cell specific HSF1 deleted mice is mediated through CD8+ T cells since treatment of these tumor-bearing mice with anti-CD8 antibody reversed the suppressive effects of HSF1-deficient CD8+ T cells on tumor growth. Finally, we successfully demonstrated the additive effects of HSF1 deletion and immune checkpoint inhibition therapy in tumor clearance. Taken together, HSF1 can be a potential therapeutic target to overcome the limitations of existing cancer therapies, and further studies will be directed towards exploring HSF1-mediated modulation of T cell metabolism as an emerging option for improvement of immunotherapy in order to generate anti-tumor CD8+ T cells with superior efficacy and enhanced survival.