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#36183155   2022/10/01 To Up

MTAP deficiency contributes to immune landscape remodeling and tumor evasion.

Methylthioadenosine phosphorylase (MTAP) deficiency occurs in various malignancies and is associated with poor survival in cancer patients. However, the mechanisms underlying tumor progression due to MTAP loss are yet to be elucidated. Utilizing integrated analyses of the transcriptome, proteome, and secretome, we demonstrated that MTAP deficiency alters tumor-intrinsic, immune-related pathways and reprograms cytokine profiles toward a tumor-favorable environment. Additionally, MTAP-knockout cells exhibited a marked increase in the immune checkpoint protein PD-L1. Upon co-culturing primary T cells with cancer cells, 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 a modest increase in average volume of tumors derived from MTAP-deficient cells than that of MTAP-proficient tumors. Surprisingly, a remarkable increase in tumor size was 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, MTAP-deficient tumors were found to display decreased immune infiltrates with lower proportions of both T lymphocytes and natural killer cells and higher proportions of immunosuppressive cells as compared to MTAP-expressing tumor xenografts. Taken together, our results suggest that MTAP deficiency restructures the tumor immune microenvironment, promoting tumor progression and immune evasion. This article is protected by copyright. All rights reserved.
Wen-Hsin Chang, Ssu-Wei Hsu, Jun Zhang, Ji-Min Li, David D Yang, Chih-Wei Chu, Estelle E Yoo, Weici Zhang, Sung-Liang Yu, Ching-Hsien Chen

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