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IL-1R1 Blockade Boosts CD40 Agonist Immune Responses but Fails to Improve Efficacy or Reduce Hepatotoxicity in
Akash Boda1, Irfan N Bandey2, Saikat Chowdhury2
1Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
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.
Insights
Blocking the IL-1 pathway with agonistic CD40 antibodies did not improve pancreatic cancer treatment and worsened liver toxicity. Ly6G+ immune cells showed an anti-tumor role, contrary to expectations.
Area of Science:
- Immunology
- Oncology
- Translational Medicine
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has dismal survival rates and limited therapeutic options.
- Agonistic CD40 antibodies show promise but have modest efficacy and significant hepatotoxicity in clinical trials.
- Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) are implicated in both tumor immunosuppression and treatment-related liver toxicity.
Purpose of the Study:
- To investigate the impact of IL-1 receptor 1 (IL-1R1) blockade on the efficacy and toxicity of agonistic CD40 antibody therapy in PDAC.
- To determine the role of PMN-MDSCs in PDAC immune responses and treatment outcomes.
Main Methods:
- Utilized orthotopic PDAC mouse models to assess therapeutic interventions.
- Administered agonistic CD40 antibodies alone, IL-1R1 blockade alone, or in combination.
- Analyzed immune cell populations, including Ly6G+ cells, and evaluated tumor growth and survival.
Main Results:
- Agonistic CD40 antibody therapy alone activated the immune system and prolonged survival in PDAC models.
- IL-1R1 blockade monotherapy suppressed immune responses and accelerated tumor growth.
- Combination therapy did not enhance anti-tumor efficacy and exacerbated liver toxicity, with Ly6G+ cell depletion reducing treatment effectiveness.
Conclusions:
- IL-1 signaling plays a complex role in PDAC immunity, with Ly6G+ cells exhibiting an anti-tumor function.
- IL-1R1 blockade is not recommended as monotherapy or in combination with agonistic CD40 antibodies for PDAC clinical trials due to lack of efficacy and increased toxicity.
