High Antigenicity for T_reg Cells Confers Resistance to PD-1 Blockade Therapy via High PD-1 Expression in T_reg Cells

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.