Blockade of CTLA-4 and PD-1 Enhances Adoptive T-cell Therapy Efficacy in an ICOS-Mediated Manner

Adoptive transfer of tumor-reactive T cells (ACT) has led to modest clinical benefit in the treatment of solid tumors. Failures with this therapy are primarily due to inadequate infiltration and poor function of adoptively transferred cells in the tumor microenvironment. To improve the efficacy of ACT, we combined ACT with dual blockade of CTLA-4 and PD-1. Treatment with anti-CTLA-4 plus anti-PD-1 compared with monotherapy resulted in durable antitumor responses, enhanced effector function of ACT, utilizing PMEL-1 transgenic (Tg⁺) CD8⁺ T cells, and improved survival. Using PMEL-1ICOS^-/- mice, we showed that deletion of the inducible T-cell costimulator (ICOS) receptor abolished the therapeutic benefits, with selective downregulation of Eomesodermin (Eomes), interferon gamma (IFNγ), and perforin. Higher expression of IFNγ and Eomes was noted in human ICOS^hi CD8⁺ T cells compared with ICOS^low counterparts. Together, our data provide direct evidence that ACT combined with immune-checkpoint therapy confers durable antitumor responses, which largely depended on CD8⁺ T-cell-intrinsic expression of ICOS. Our study provides a foundation of testing combinatorial therapy of ACT of CD8 T cells and dual blocking of CTLA-4 and PD-1 in patients with melanoma.