Regulatory T cells expressing abundant CTLA‐4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer

: FOXP3+ regulatory T (Treg) cells suppress anti-tumor immunity. The suppression of Treg cells is regulated by cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), whose expression on the cell surface is tightly regulated. Here we found that Treg cells expressing abundant CTLA-4 on the cell surface (surface-CTLA-4+ Treg) were expanded in human head and neck cancer tissues. RNA sequencing of surface-CTLA-4+ and surface-CTLA-4- Treg cells infiltrating human head and neck cancer tissues revealed that surface-CTLA-4+ Treg cells have a previously undescribed gene expression profile correlating to cell cycle, cell proliferation, and DNA replication. Moreover, surface-CTLA-4+ Treg cells were PD-1+ , actively proliferated and associated with CD45RA- FOXP3high Treg cells with strong suppressive function. Thus, surface-CTLA-4+ Treg cells with a proliferative gene expression signature and phenotype are key features of head and neck cancer. Targeting surface-CTLA-4+ Treg cells might be new strategies to evoke effective immune responses to head and neck cancer.