IL-1R1 Blockade Enhances CD40 Agonist-Mediated Immune Responses but Fails to Increase Efficacy or Mitigate Hepatotoxicity in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal 5-year survival rate of only 10% in the United States. While immune checkpoint blockade (ICB) has shown efficacy in many solid tumors, PDAC remains largely unresponsive. Agonistic CD40 antibodies can activate PDAC-associated myeloid cells, enhancing innate and adaptive anti-tumor immunity. However, clinical trials with agonistic CD40 antibodies have demonstrated only modest efficacy and significant hepatotoxicity. We previously reported that IL-1 pathway blockade enhances CD40 agonist efficacy against melanoma by depleting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs; CD11b Ly6C Ly6G ). Since PMN-MDSCs also cause liver toxicity. This study investigates the impact of IL-1R1 blockade on the efficacy and toxicity of CD40 agonist therapy in PDAC. We found that treatment with an agonistic CD40 antibody induced immune activation and significantly prolonged survival in orthotopic PDAC-bearing mice. The transcriptomic profile revealed that IL-1R1 blockade as monotherapy downregulated innate and adaptive immune response and exacerbated tumor growth. However, the combination therapy of agonistic CD40 antibody and IL-1R1 blockade upregulated several immune-related pathways (GO enrichment analysis), including JAK-STAT signaling, antigen processing, and presentation, natural killer cell mediated cytotoxicity, boosted innate and adaptive immune responses, compared to CD40 agonist treatment alone. Paradoxically, despite these immunostimulatory effects, IL-1R1 blockade failed to improve the overall anti-tumor efficacy of CD40 agonist therapy and exacerbated liver toxicity. Liver toxicity was assessed by serum ALT and AST levels, and transcriptomic profiling of the liver revealed several pathways related to immune infiltration, liver metabolism, viral carcinogenesis and alcoholic liver disease were associated with hepatotoxicity. To further investigate the role of PMN-MDSCs in PDAC and understand the failure of anti-IL-1R1 therapy, we depleted these cells using an anti-Ly6G antibody in mice treated with an agonistic CD40 antibody. Unexpectedly, Ly6G depletion reduced the efficacy of CD40 agonist therapy, suggesting that, contrary to expectations, Ly6G immune cells (PMN-MDSCs or neutrophils) exhibit an anti-tumor rather than an 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 a monotherapy or in combination with CD40 agonist antibodies, in future clinical trials for PDAC.