IL-18 engineered to avoid decoy-receptor binding enhances tumor rejection by anti-CTLA-4 in kidney cancer models through immune microenvironment remodeling.

The cytokine interleukin-18 (IL-18) has immunostimulatory effects but is negatively regulated by a secreted binding protein, IL-18BP, that limits IL-18’s anti-cancer 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 investigate the therapeutic potential of DR-18 in renal cell carcinoma (RCC). 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 intra-tumoral enrichment and clonal expansion of effector CD8+ T cells, decreased regulatory T cell levels, and enrichment of pro-inflammatory, anti-tumor myeloid cell populations, as assessed by scRNA- and scTCR-seq. We performed scRNA-seq and scTCR-seq on Renca tumors impanted subcutaneously into Balb/c mice and treated with one of the following regimens: PBS; DR-18; anti-CTLA-4; or the combination ("Combo") of DR-18 and anti-CTLA-4. Tumor tissue from 3 mice per treatment condition were pooled for sequencing.