Abstract
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.1900940

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