Microbiome metabolites modulate MAIT cell response to immune checkpoint blockade in non-small cell lung cancer (NSCLC) 3096

Abstract Description Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognize the microbial metabolite 5OPRU when presented on MR1, a non-classical MHC-like molecule. Two subsets of MAIT cells have been described: Tbet+ MAIT1, which infiltrate the tumor microenvironment (TME) and may exert anti-tumor effects via IFNγ and granzyme B, and RORγt+ MAIT17, which produce IL-17A which may hinder anti-tumor immunity. The commensal microbiome influences response to immune checkpoint blockade (ICB) therapy in NSCLC. However, the role of MAIT subsets as a mediator of this process remains unclear. An orthotopic lung tumor model in B6/MAIT-CAST mice was used to characterize the effects of microbial metabolites on MAIT subsets during ICB therapy. 5OPRU was administered intranasally with ICB and appropriate controls. Mice treated with 5OPRU alone developed larger tumors associated with increased IL-17A+ MAIT17 and dysfunctional PD1+ MAIT1 populations. In contrast, mice receiving ICB + 5OPRU had smaller tumors compared with ICB alone and exhibited a higher frequency of cytotoxic (IFNγ+, granzyme B+, PD1-) MAIT1. Conventional CD4/CD8 T cells and unconventional γδT/NKT cells showed no cytokine differences across groups, suggesting these results are MAIT-dependent. These findings suggest that microbial metabolites like 5OPRU modulate MAIT subsets and may enhance anti-tumor responses during ICB therapy. Funding Sources Canadian Institutes of Health Research (CIHR). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)