ABSTRACT
BACKGROUND: Cell therapy has shown promise in the treatment of certain solid tumors, but its efficacy may be limited by inhibition of therapeutic T cells by the programmed cell death protein-1 (PD-1) receptor. Clinical trials are testing cell therapy in combination with PDCD1 disruption or PD-1-axis blockade. However, preclinical data to support these approaches and to guide the treatment design are lacking. METHODS: Mechanisms of tumor regression and interaction between cell therapy and PD-1 blockade were investigated in congenic murine tumor models based on targeting established, solid tumors with T-cell receptor T cells directed against tumor-restricted, non-self antigens (ie, tumor neoantigens). RESULTS: In solid tumor models of cell therapy, PD-1 blockade mediated a reproducible but non-synergistic increase in tumor regression following adoptive T-cell transfer. Tumor regression was associated with increased tumor infiltration by endogenous T cells but not by transferred T cells. The effect was independent of PD-1 receptor expression by transferred T cells and was dependent on the endogenous T-cell repertoire and on tumor antigenicity. PD-1 blockade primarily induced cell state changes in endogenous tumor-antigen-specific T cells rather than transferred T cells. CONCLUSIONS: Together, these findings support the concept that PD-1 blockade acts primarily through endogenous rather than transferred T cells to mediate a non-synergistic antitumor effect in solid tumor cell therapy. These findings have important implications for strategies to leverage PD-1 receptor disruption or blockade to enhance the efficacy of cell therapy.
