Ching‐Hsien Chen

Methylthioadenosine phosphorylase (MTAP) deficiency occurs in various malignancies and is associated with poor survival in cancer patients. However, the mechanisms underlying tumour 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 tumour‐intrinsic, immune‐related pathways and reprograms cytokine profiles towards a tumour‐favourable 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 tumour models, we showed a modest increase in average volume of tumours derived from MTAP‐deficient cells than that of MTAP‐proficient tumours. Surprisingly, a remarkable increase in tumour size was observed in humanized mice bearing MTAP‐deficient tumours, as compared to their MTAP‐expressing counterparts. Following immunophenotypic characterization of tumour‐infiltrating leukocytes by mass cytometry analysis, MTAP‐deficient tumours 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 tumour xenografts. Taken together, our results suggest that MTAP deficiency restructures the tumour immune microenvironment, promoting tumour progression and immune evasion.