IL-1R1 Blockade Boosts CD40 Agonist Immune Responses but Fails to Improve Efficacy or Reduce Hepatotoxicity in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) has a poor survival rate and limited treatments. Agonistic CD40 antibodies are promising, but clinical trials have shown only modest efficacy and significant hepatotoxicity. We previously reported that IL-1 pathway blockade enhances agonistic CD40 antibody efficacy against melanoma by depleting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs; CD11b ⁺ Ly6C ⁺ Ly6G ⁺ ). Because PMN-MDSCs also cause liver toxicity, we investigated the impact of IL-1R1 blockade on the efficacy and toxicity of agonistic CD40 antibody therapy in PDAC. Agonistic CD40 antibody therapy induced immune activation and significantly prolonged survival in orthotopic PDAC-bearing mice. IL-1R1 blockade monotherapy downregulated innate and adaptive immune response and exacerbated tumor growth. Although combination therapy upregulated several immune-related pathways and boosted innate and adaptive immune responses. IL-1R1 blockade failed to improve the overall antitumor efficacy of agonistic CD40 antibody therapy and exacerbated liver toxicity. Ly6G ⁺ cell depletion in mice reduced the efficacy of agonistic CD40 antibody therapy, suggesting that Ly6G⁺ immune cells (PMN-MDSCs or neutrophils) exhibit an antitumor rather than immunosuppressive role in PDAC. Our findings underscore the complex role of IL-1 signaling in modulating immune responses in PDAC and caution against pursuing IL-1R1 blockade, either as monotherapy or combined with agonistic CD40 antibodies, in clinical trials for PDAC.