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Background Mucosal-associated invariant T (MAIT) cells are an innate-like T cell subset, defined by semi-invariant TCRα chains that recognize microbial-derived vitamin B metabolites presented by the non-polymorphic MR1 molecule. The TCRα chains expressed by MAIT cells predominantly utilize TRAV1-2-TRAJ33/20/12. 1Upon activation, they produce IFN-γ, TNF-α, IL-17, and cytotoxic molecules such as granzyme B and perforin. In cancer, MAIT cells exhibit both anti- and pro-tumor functions, with their frequency and activation status in blood or tumors correlating with prognosis in colorectal, hepatocellular, and lung cancers.Methods The Tempus de-identified real-world, multi-modal database was analyzed for solid tumors with TCR sequencing data (N=190,189), defining MAIT-associated TCRα chains by TRAV1-2 and TRAJ33 presence or clonotypes from Loh et al. 1 MAIT cell abundance was determined by the total number of clonotypes mapped to MAIT TCRα chains. In multivariate models, total TCRα counts adjusted for overall T cell infiltration. Univariate testing assessed MAIT cell prevalence across clinical and demographic variables, including age, race, sex, microsatellite instability (MSI), and PD-L1 status. Additionally, multivariate linear models were utilized, adjusting for covariates and total detected TCRα abundance. RNA-seq from matched samples was used to correlate MAIT cell abundance with T cell markers such as GZMB and MR1. MAIT cell abundance was tested across each indication for prognostic association, along with co-occurrence of bacterial and viral strains, including HPV and EBV, detected through next-generation sequencing.Results MAIT cell abundance was highest in tumors of mucosal origin, particularly colorectal and gastroesophageal cancers, compared to non-mucosal tumors such as lung and breast cancers. Pan-cancer, higher MAIT cell levels were statistically significant in younger patients, males, and non-smokers, independent of total TCRα counts ( figures 1 and 2; p < 0.001). In colorectal cancer (N=13,349), MSI status was associated with reduced MAIT cell abundance (p < 0.001). MAIT cells were lower in non-small cell lung cancer patients with high PD-L1 status by IHC (TPS > 50%; p < 0.001). MAIT cells correlated with GZMB and MR1 expression across tumor types. Distinct patterns of MAIT cell abundance were associated with specific pathogen co-occurrence, including increased frequency in HPV-positive HNSCC.Conclusions This study used intratumoral TCR-seq on real-world data to show MAIT cell prevalence is linked to cancer development and therapy response across multiple tumor types. As a unique T cell subset with MHC-independent activation, MAIT cells may serve as promising immunotherapy targets and biomarkers for the tumor immune microenvironment.Reference Kurioka A, Jahun AS, Hannaway RF, Walker LJ, Fergusson JR, Sverremark-Ekström E, Klenerman P. Shared and distinct phenotypes and functions of human CD161++ Vα7.2+ T cell subsets. The Journal of Immunology. 2020;204(5):1119–1129. https://doi.org/10.4049/jimmunol.1900940Abstract 133 Figure 1Boxplot of MAIT cells by ageAbstract 133 Figure 2Forest pot of GLM coefficients for all indications