Role of heat shock factor 1 (HSF1) on activation-induced metabolic reprogramming of T cells

Abstract

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 or enforcing fatty acid oxidation, enhances the formation of more efficient anti tumor CD8+ T-cells. Since, HSF1 is involved in cellular metabolism, in this study, we explored the strategies to manipulate (or reprogram) the metabolic pathways used by the immune system to improve anti-tumor immunity. We observed that deletion of HSF1 profoundly affects the metabolic reprogramming of naive CD8+ T cells upon anti-CD3/CD28 stimulation in vitro. Furthermore, HSF1-deficient T cells show reduced oxygen consumption rate and extracellular acidification rate upon activation. These effects correspond to delayed T-cell receptor signaling and slower activation of naive T cells preventing them from moving towards early exhaustion stage resulting in improved longevity. In addition, we detected delayed initiation of colon cancer MC38 tumors that was implanted into a T-cell specific HSF1 deficient mice compared to wild-type mice. Finally, we confirmed that the delay in tumorigenesis is mediated through CD8 response since treatment of above tumor bearing mice with anti-CD8 antibody reversed the suppressive effects of HSF1 deficient CD8 T cells on tumor growth. Taken together, HSF1 can be a potential therapeutic target to overcome the limitations with existing cancer therapies and further studies will be directed towards exploring impact of HSF1 on checkpoint blockade.