To improve outcomes of adoptive T cell therapy (ACT) for solid tumors, Shi et al. investigated dual blockade of CTLA-4 and PD-1 (CPB) with ACT in a transgenic gp100-CD8+ T cell tumor model. Combination of ACT plus CPB prolonged survival, increased tumor-specific CD8+ T cell effector function, and induced high levels of ICOS, compared to ACT or CPB alone. ICOS signaling in CD8+ TILs increased levels of IFNγ, perforin, and Eomes but not IL-2 or TNFα, and deletion of ICOS abrogated the therapeutic benefits. Combining CD8+ ACT with CPB may have therapeutic benefit via stimulation of intrinsic ICOS signaling in CD8+ T cells.
Contributed by Katherine Turner
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 to 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 co-stimulator (ICOS) receptor abolished the therapeutic benefits, with selective downregulation of Eomesodermin (EOMES), interferon gamma (IFN-gamma), and perforin. Higher expression of IFN-gamma and EOMES were noted in human ICOShi CD8+ T cells compared to ICOSlow 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.