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(-) FOXP3(high) 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. What's new? Regulatory T (Treg) cells have been shown to suppress anti-tumor immunity. CTLA-4 is key in controlling Treg function, but its importance in head and neck cancer remains unclear. Here, the authors found that Treg cells with abundant CTLA-4 on the cell surface (surface-CTLA-4(+) Treg) were expanded in human head and neck cancer. This is surprising because most CTLA-4 is generally expressed intracellularly. Surface-CTLA-4(+) Treg cells in human head and neck cancer highly expressed previously-undescribed genes correlated to cell cycle, cell proliferation, and DNA replication. Targeting surface-CTLA-4(+) Treg cells might lead to new strategies for eliciting anti-tumor immunity in human cancer.