Exploiting metabolism of vaccine-elicited T cells to enhance tumor immunotherapy

Abstract

Abstract Given the highly glycolytic nature of most cancers, glycolysis inhibition remains a strong potential treatment strategy. However, effective glycolysis blockade may also inhibit the function and survival of infiltrating T cells. Unlike T cells activated by infections and cancer, T cells activated by subunit vaccination do not rely on aerobic glycolysis, either during their initial proliferative burst or thereafter. Instead, these vaccine-elicited T cells primarily rely on mitochondrial metabolism of fatty acids and OXPHOS. Thus, we hypothesize that vaccine-elicited T cells will maintain anti-cancer therapeutic efficacy even under conditions of glycolytic inhibition. Additionally, vaccine-elicited T cells are characterized by robust expression of the transcription factor Tcf1, which has been shown to identify a stem-like pool of T cells capable of sustaining an anti-cancer response. We show that a therapeutic regimen combining subunit vaccination with glycolysis inhibition significantly impairs tumor growth in mice. These effects are further enhanced by the addition of clinically-relevant αPD-1 inhibitors. Collectively, these data show the potential of controlling tumor progression by exploiting the distinct metabolic and transcriptional program of vaccine-elicited T cells through a novel combination immuno/metabolomic therapeutic regimen.