Cutting Edge: Promoting T Cell Factor 1⁺ T Cell Self-Renewal to Improve Programmed Cell Death Protein 1 Blockade

Immune checkpoint blockade is limited by resistance to treatment, with many patients not achieving durable antitumor responses. Self-renewing (T cell factor 1⁺ [TCF1⁺]) CD8⁺ T cells have recently been implicated in efficacy of anti-programmed cell death protein 1 (anti-PD-1). Mice challenged with syngeneic tumors were treated with anti-PD-1 and/or a reversible inhibitor of PI3K δ, designed to promote T cell self-renewal. Growth of tumors in untreated mice was characterized by waning proportions of TCF1⁺ T cells, suggesting self-renewing T cells become limiting for successful immunotherapy. Higher proportions of TCF1⁺ T cells in tumor and blood correlated with better control of tumor growth. Combining anti-PD-1 and inhibitor of PI3K δ conferred superior protection compared with either monotherapy and was associated with higher frequency of TCF1⁺ T cells in tumor and blood compared with anti-PD-1 alone. These findings reveal predictive importance of self-renewing T cells in anti-tumor immunity and suggest that resistance-directed strategies to enhance T cell self-renewal could potentiate the efficacy of PD-1 blockade.