Decoy-resistant IL-18 reshapes the tumor microenvironment and enhances rejection by anti–CTLA-4 in renal cell carcinoma

The cytokine IL-18 has immunostimulatory effects but is negatively regulated by a secreted binding protein, IL-18BP, that limits IL-18's anticancer efficacy. A decoy-resistant form of IL-18 (DR-18) that avoids sequestration by IL-18BP while maintaining its immunostimulatory potential has recently been developed. Here, we investigated the therapeutic potential of DR-18 in renal cell carcinoma (RCC). Using pantumor transcriptomic data, we found that clear cell RCC had among the highest expression of IL-18 receptor subunits and IL18BP of tumor types in the database. In samples from patients with RCC treated with immune checkpoint inhibitors, IL-18BP protein expression increased in the tumor microenvironment and in circulation within plasma in nonresponding patients, and it decreased in the majority of responding patients. We used immunocompetent RCC murine models to assess the efficacy of DR-18 in combination with single- and dual-agent anti-PD-1 and anti-CTLA-4. In contrast to preclinical models of other tumor types, in RCC models, DR-18 enhanced the activity of anti-CTLA-4 but not anti-PD-1 treatment. This activity correlated with intratumoral enrichment and clonal expansion of effector CD8+ T cells, decreased Treg levels, and enrichment of proinflammatory antitumor myeloid cell populations. Our findings support further clinical investigation of the combination of DR-18 and anti-CTLA-4 in RCC.