No abstract

Highlights d Inactivation of T cell autophagy results in enhanced tumor rejection d T cells deficient in autophagy show increased glucose uptake and lactate production d Reduction in SAM transcriptionally reprograms immune cells toward effector memory

Immune regulatory metabolites are key features of the tumor microenvironment (TME), yet with a few exceptions, their identities remain largely unknown. Here, we profiled tumor and T cells from tumor and ascites of patients with high-grade serous carcinoma (HGSC) to uncover the metabolomes of these distinct TME compartments. Cells within the ascites and tumor had pervasive metabolite differences, with a notable enrichment in 1-methylnicotinamide (MNA) in T cells infiltrating the tumor compared with ascites. Despite the elevated levels of MNA in T cells, the expression of nicotinamide N-methyltransferase, the enzyme that catalyzes the transfer of a methyl group from S-adenosylmethionine to nicotinamide, was restricted to fibroblasts and tumor cells. Functionally, MNA induces T cells to secrete the tumor-promoting cytokine tumor necrosis factor alpha. Thus, TME-derived MNA contributes to the immune modulation of T cells and represents a potential immunotherapy target to treat human cancer.

Macroautophagy/autophagy is a critical regulator of adaptive T cell immunity and homeostasis. However, the role of T cell autophagy in regulating antitumor immune responses is less clear. In a recent study, we showed that deletion of the essential autophagy genes Atg5, Atg14, or Atg16l1 in host tissues dramatically impairs growth of autophagy-competent syngeneic tumors. We further demonstrated that CD8 + T cells lacking Atg5 acquire an effector memory phenotype and produce more IFNG/ IFN-γ (interferon gamma) and TNF/TNF-α (tumor necrosis factor). These phenotypic changes are accompanied by enhanced glucose metabolism that results in alterations in histone methylation, and upregulation of glycolytic and immune response genes. In accordance with this, we observed control of tumor growth in autophagy-competent mice after adoptive transfer with a sub-therapeutic dose of atg5-/-T cells. Collectively, we discovered a unique, cell-autonomous role for T cell autophagy in the metabolic control of antitumor immunity.