MAIT cells and MR1 play an immunosuppressive role in glioblastoma through the induction of neutrophils and MDSCs

Background Major histocompatibility complex class I-related protein (MR1) is an antigen-presenting molecule for Mucosal-Associated Invariant T (MAIT) cells. Although the expression level of the MR1 gene was reported to correlate with worse survival in glioma patients, a detailed mechanism of this association has not been elucidated. This study aimed to understand the mechanism by which MR1 levels affect glioblastoma (GBM) patient survival and any potential involvement of MAIT cells in this mechanism. Methods Multi-layered gene expression analysis, including direct sequence alignment and search, were conducted on The Cancer Genome Atlas (TCGA)-GBM data. The immunological impact of MAIT cells in GBM was evaluated using multiple analytical methods, including statistical correlation analysis and Gene Set Enrichment Analysis. Pan-cancer TCGA data was utilized to evaluate the role of MAIT cells in other cancers. Results Intact MR1 was expressed in a broad spectrum of cell types in GBM, and its expression level was inversely correlated with the survival of GBM patients. Significant positive correlations were found between the expression of MR1 , the amount of MAIT cell infiltration, and the activity of tumor-associated neutrophils (TANs)/myeloid-derived suppressor cells (MDSCs) in GBM. Simultaneously, the activity of TANs/MDSCs was significantly inversely correlated with the survival of GBM patients. Similar associations between MAIT/MR1 and TANs/MDSCs were observed in four additional cancer types. Conclusions Our observations shed light on the possible immunosuppressive role of MAIT cells and MR1 in GBM. It was indicated that MR1 up-regulation leads to activation of MAIT cells, which in turn induce the activation and infiltration of TANs/MDSCs. Our results suggest the existence of a novel immunosuppressive MAIT/MR1-TAN/MDSC pathway whose activation contributes to the poorer prognosis of GBM patients and which necessitates novel strategies to counteract this immunosuppressive role of MAIT cells. Key points Importance of the study MR1-restricted MAIT cells are unconventional T cells that have the potential to regulate tumor immunity. However, their immunobiology in GBM has not been understood. MR1 expression levels were reported to correlate with worse survival in glioma patients, while the involvement of MAIT cells in the correlation was not clear. Using the TCGA-GBM data, we observed a fraction of GBM patients have MAIT cells in the tumor and significant correlations between the expression level of MR1, MAIT cell infiltration, and activities of TANs/MDSCs. Genes involved in multiple TAN/MDSC-mediated immunosuppressive pathways were upregulated in MAIT-positive patients. Importantly, both MR1 expression levels and TAN/MDSC activation negatively correlated with patient survival. The results suggest the existence of a novel immunosuppressive MAIT/MR1-TAN/MDSC pathway whose activation contributes to the poorer prognosis of GBM patients, and which provides novel strategies to counteract immune suppression in GBM patients. ### Competing Interest Statement The authors have declared no competing interest.