Immune checkpoint blockade unleashes Mucosal Associated Invariant T (MAIT) cells in tumor microenvironment of NSCLC patients

Abstract Mucosal associated invariant T (MAIT) cells are innate like T-cells that recognise non-peptide metabolite antigens presented on monomorphic MHC related-1 (MR1) making them an attractive off the shelf tool for cancer immunotherapy. In this study, we investigate function of MAITs in tumor microenvironment neoadjuvant anti-PD1 treated lung patients (NCT02259621). Paired single cell RNA/TCR sequencing analysis revealed oligoclonal expansion comprising canonical TRAV1–2 +and non-canonical −. TCR capture from MAIT clonotypes confirmed their vitro recognition 5-OP-RU, a bacteria derived riboflavin derivative. However, nature recognised by remains poorly understood. On mining transcriptional profiles MAITs, observed high clonal amplification whereas expressed strong activation/exhaustion gene signature. This suggests both these populations different types antigens, differentially activated, and respond to immune checkpoint blockade (ICB), being highly dysfunctional. Using bacterial 16S RNA amplicon metagenomics sequencing, seek identify microbial metabolomic signatures with activation response ICB. Our findings will provide further insights into ligands mechanisms MR1 dependent killing tumor. Investigating role unconventional ICB has potential reveal new tumor-associated which could open up avenues innovative combination immunotherapies.