Abstract
Regulatory T (T(reg)) cells have an immunosuppressive function, and programmed death-1 (PD-1)-expressing T(reg) cells reportedly induce resistance to PD-1 blockade therapies through their reactivation. However, the effects of antigenicity on PD-1 expression in T(reg) cells and the resistance to PD-1 blockade therapy remain unclear. Here, we show that T(reg) cells gain high PD-1 expression through an antigen with high antigenicity. Additionally, tumors with high antigenicity for T(reg) cells were resistant to PD-1 blockade in vivo due to PD-1(+) T(reg)-cell infiltration. Because such PD-1(+) T(reg) cells have high cytotoxic T lymphocyte antigen (CTLA)-4 expression, resistance could be overcome by combination with an anti-CTLA-4 monoclonal antibody (mAb). Patients who responded to combination therapy with anti-PD-1 and anti-CTLA-4 mAbs sequentially after primary resistance to PD-1 blockade monotherapy showed high T(reg) cell infiltration. We propose that the high antigenicity of T(reg) cells confers resistance to PD-1 blockade therapy via high PD-1 expression in T(reg) cells, which can be overcome by combination therapy with an anti-CTLA-4 mAb.