Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity 2100

Abstract Description Tumor-derived metabolites are known to have immunosuppressive impacts in the tumor microenvironment (TME). Methylmalonic acid (MMA), a byproduct of propionate metabolism, was shown to promote tumor progression via its direct effects in tumor cells. How MMA impacts other TME components that affect tumorigenesis has not been studied. The proliferation and function of CD8+ T cells, adaptive anti-cancer immune cells, is known to decline with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that increase MMA levels. Thus, we hypothesized that a cause-and-effect relationship exists between these two aging features, whereby increased MMA levels lead to a suppression of CD8+ T cell immunity. Here we show that such relationship exists, where treatment of primary CD8+ T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming marked by an increase in the exhaustion regulator, TOX. Accordingly, MMA upregulated exhaustion markers in CD8+ T cells and decreased their effector function, which was associated with defects in mitochondrial function, increased ROS production, and reprogramming of central carbon metabolism. Consequently, we observed that MMA abrogated anti-tumor immunity in vitro and in vivo. Collectively, our data reveal a previously unknown immunomodulatory role of MMA, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer. Funding Sources This work was directly supported by the Pathway to Independence Award from NCI (R00CA218686; R00CA218686-04S1) to APG. This work was also supported by T32 CA233399 (RSH); P01-CA250984 (JLC); 5P01CA120964 (JMA); 5P30CA006516 (JMA); DP2AG0776980 (APG); RSG-22-164-01-MM (APG); R21AG083720 (APG); and R01CA279023 (APG). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)