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. 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. [ABSTRACT FROM AUTHOR]