Metabolic Control of CD8 + T Cell Fate Decisions and Antitumor Immunity

摘要

CD8 + T cells are central players in controlling infections and cancer. Longevity, functionality, and metabolic fitness are critical determinants of T cell efficacy in cancer immunotherapy. Tumor-infiltrating CD8 + T cells undergo metabolic ‘exhaustion’ in the nutrient- and oxygen-deprived tumor microenvironment (TME). Thus, reprograming CD8 + T cell metabolism may provide important therapeutic strategies for cancer treatment. Indeed, the adoptive transfer of memory CD8 + T cells with sustained metabolic fitness may yield better antitumor protection in both mouse models and the clinic. Here, we discuss recent progress on how cellular metabolism is linked to CD8 + T cell fate decisions and on how metabolic intermediates can impact gene expression via modulation of the epigenome. We examine the feasibility of developing potential strategies to improve antitumor immunity through the modulation of T cell metabolic activity. Highlights Important insights have been obtained linking CD8 + T cell activation, fate decision and metabolic reprogramming. Quiescent na?ve CD8 + T cells rely on oxidative phosphorylation (OXPHOS), and activated CD8 + T cells engage OXPHOS, glutaminolysis, and glycolysis, important for the acquisition of effector functions. Central memory CD8 + cells (Tcm) preferentially engage de novo fatty acid (FA) synthesis to fuel FA oxidation and, thus, enhance the spare respiratory capacity of mitochondria, providing survival advantages. Recent studies demonstrated that mitochondrial biogenesis, dynamics, and architecture control CD8 + T cell memory formation. Tumor-infiltrating lymphocytes (TILs) display dysregulated mitochondrial architecture and activity, which may underlie their functional decline. Metabolic intermediates are important regulators of chromatin- or histone-modifying enzymes, and cellular metabolism might dictate CD8 + T cell fate via the epigenetic regulation of gene expression. Metabolic competition in the TME can be a major determinant of TIL functional performance. Thus, it is therapeutically relevant to modulate T cell metabolic activity to achieve improved antitumor immunity.