Targeting mucosal associated invariant T (MAIT) cells via the gut microbiome as a novel immunotherapy for pancreatic cancer liver metastasis 4562

Abstract Description Pancreatic cancer liver metastasis (PCLM) occurs in 50% of pancreatic cancer patients. Mucosal-associated invariant T (MAIT) cells are innate T cells restricted to microbial riboflavin-derived antigens presented by MR1 on antigen-presenting cells (APCs). MAIT cell dysfunction, including a shift toward the pro-tumorigenic MAIT17 subtype, has been implicated in increased tumor burden. Microbial antigens from the gut can migrate to the liver, where MR1 on APCs triggers aberrant MAIT activation and dysregulation. We hypothesize that the PCLM tumor microenvironment (TME) drives MAIT cell dysfunction, promoting tumor burden, and that depleting the gut microbiome rescues MAIT dysfunction and reduces tumor burden. Using a hemispleen injection PCLM model, we found that MR1 is enriched in the tumor and TME and promotes MAIT cell dysfunction via exhaustion and a MAIT17 shift. MR1 KO mice, lacking MAIT cells, showed significantly reduced tumor burden compared to WT mice. Antibiotic-treated (PCLM+ABX) mice, with depleted gut microbiomes, also exhibited reduced tumor burden and shifted MAIT cells from pro- to anti-tumor phenotypes in MR1 WT mice but not in MR1 KO mice. These findings suggest that MAIT cells can be therapeutically modulated via the gut microbiome to enhance anti-tumor immunity in PCLM. Funding Sources Henry Ford Cancer Immunology Research Program [T71016] to QSM and [T71017] LZ, and NIH/NCI [1R01CA284740] to QSM and LZ. Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)