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

Boda, A.; Bandey, I. N.; CHOWDHURY, S.; Aggarwal, S.; Reddy, M. v.; Fowlkes, N. W.; Roszik, J.; Curran, M. A.; Morris, V. K.; Kopetz, S.; Singh, M.

doi:10.1101/2025.02.23.639774

bioRxiv · 10.1101/2025.02.23.639774

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

Boda, A.·Bandey, I. N.·CHOWDHURY, S.·Aggarwal, S.·Reddy, M. v.·Fowlkes, N. W.·Roszik, J.·Curran, M. A.·Morris, V. K.·Kopetz, S.·Singh, M.

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Abstract

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.

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Boda, A., Bandey, I. N., CHOWDHURY, S., Aggarwal, S., Reddy, M. v., Fowlkes, N. W., Roszik, J., Curran, M. A., Morris, V. K., Kopetz, S., Singh, M.. 2025-02-27. IL-1R1 Blockade Enhances CD40 Agonist-Mediated Immune Responses but Fails to Increase Efficacy or Mitigate Hepatotoxicity in Pancreatic Cancer. https://doi.org/10.1101/2025.02.23.639774

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