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 investigated the therapeutic potential of DR-18 in renal cell carcinoma (RCC). Using pan-tumor 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 RCC patients treated with immune checkpoint inhibitors, IL-18BP protein expression increased in the tumor microenvironment and circulating in plasma in non-responding patients and 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 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. Our findings support further clinical investigation of the combination of DR-18 and anti-CTLA-4 in RCC.
JCI insight. 2024 Nov 19 [Epub ahead of print]
David A Schoenfeld, Dijana Djureinovic, David G Su, Lin Zhang, Benjamin Y Lu, Larisa Kamga, Jacqueline E Mann, John D Huck, Michael Hurwitz, David A Braun, Lucia Jilaveanu, Aaron M Ring, Harriet M Kluger
Section of Medical Oncology, Yale School of Medicine, New Haven, United States of America., Section of Surgery, Yale School of Medicine, New Haven, United States of America., Department of Internal Medicine, Emory Univerisity School of Medicine, Atlanta, United States of America., Department of Immunobiology, Yale School of Medicine, New Haven, United States of America., Immunotherapy Integrated Research Center, Fred Hutchinson Cancer Center, Seatlle, United States of America.