Characterization of MAIT Cells in Glioblastoma Reveals a Potential Immunosuppressive Role Through a MAIT-Neutrophil Axis

Background Glioblastoma (GBM) is the most aggressive primary brain cancer in adults and remains incurable. Mucosal-associated invariant T (MAIT) cells are unconventional T cells with a semi-invariant T cell receptor and have been shown to regulate immune responses. However, the role of MAIT cells in glioblastoma (GBM) has not been well characterized. Methods We used flow cytometry, bulk RNA-seq and scRNA-seq, and multiplexed tissue imaging to investigate the role of MAIT cells in GBM. Results Flow cytometry analysis of peripheral blood samples of GBM patients showed a significant reduction of MAIT cell frequency and the ability to produce Th1 cytokines. In bulk RNA sequencing data analysis of GBM tissues, the MAIT cell gene signature significantly correlated with poor patient survival. A scRNA-seq of CD45+ cells from 20 GBM tissue samples showed 12 (60%) were positive for MAIT cells and the enrichment of RORC-expressing MAIT17. The MAIT cell signature significantly correlated with tumor-associated neutrophil (TAN) activities. Multiple immune suppressive genes known to be used by TANs were upregulated in MAIT-positive tumors. Spatial imaging analysis of GBM tissues showed that all specimens were positive for both MAIT cells and TANs, and localized enrichment of TANs. Conclusion These findings revealed an immunosuppressive role of MAIT cells in GBM and highlighted the MAIT-TAN axis as a potential novel therapeutic target to modulate GBM’s immunosuppressive tumor microenvironment.