MTAP deficiency reshapes the tumor immune landscape in lung cancer

Abstract

Abstract Methylthioadenosine phosphorylase (MTAP) deficiency occurs in a broad range of malignancies; notably, loss of this metabolizing enzyme was reported to be associated with poor survival in cancer patients. However, the mechanisms underlying tumor progression due to MTAP loss are yet to be elucidated. Utilizing RNA-sequencing, reverse phase protein arrays, and Luminex assays, we demonstrated that MTAP deficiency alters tumor-intrinsic, immune-related pathways and reprograms cytokines toward a tumor-favorable environment in both lung and kidney cancer. In addition, MTAP-knockout cells exhibited a marked increase in the immune checkpoint protein PD-L1. Upon co-culturing primary T cells with cancer cells, we found that MTAP loss-mediated PD-L1 upregulation inhibited T cell-mediated killing activity and induced several T cell exhaustion markers. In two xenograft tumor models, we showed that the average volume of tumors derived from MTAP-deficient cells is slightly greater than that of MTAP-proficient tumors. Surprisingly, a remarkable increase in tumor size was also observed in humanized mice bearing MTAP-deficient tumors, as compared to their MTAP-expressing counterparts. Following immunophenotypic characterization of tumor-infiltrating leukocytes by mass cytometry analysis, compared to MTAP-expressing tumor xenografts, MTAP-deficient tumors was found to display decreased immune infiltrates that consist of abundant immunosuppressive cells and lower portions of both T lymphocytes and natural killer cells. Taken together, our results suggest that MTAP deficiency reconstructs the tumor immune microenvironment via cytokine reprogramming and immune remodeling, promoting tumor progression and immune evasion. This work was supported by grants funded by the Department of Defense Kidney Cancer Research Program (KCRP) W81XWH1910831 (log# KC180170) and the California UCOP Tobacco-Related Disease Research Program (TRDRP) T29IR0704.