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Updated: Apr 6, 2026
Flow Cytometry-Based Isolation and Therapeutic Evaluation of Tumor-Infiltrating Lymphocytes in a Mouse Model of Pancreatic Cancer
Published on: January 17, 2025
IL1R1 blockade augments CD40 agonist mediated immunity in pancreatic cancer
Akash R Boda1, Irfan N Bandey2, Saikat Chowdhury2
1Department of Immunology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, 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 CD40 agonist 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. The combination of an agonistic CD40 antibody and IL-1R1 blockade upregulated multiple immune-related pathways and enhanced innate and adaptive responses. However, it did not further improve CD40 efficacy or reduce liver toxicity. The efficacy of the CD40 agonist was partially dependent on CD8⁺ T cells. 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 CD40 agonist therapy did not improve pancreatic cancer treatment or reduce liver toxicity in mice. This approach is not recommended for clinical trials in PDAC.
Area of Science:
- Immunology
- Oncology
- Gastroenterology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) presents a significant therapeutic challenge with poor survival rates.
- Agonistic CD40 antibodies show promise but have demonstrated limited efficacy and notable hepatotoxicity in clinical trials.
- IL-1 pathway blockade was previously shown to enhance CD40 agonist efficacy in melanoma by reducing polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs).
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 pancreatic ductal adenocarcinoma (PDAC).
Main Methods:
- Utilized orthotopic PDAC mouse models to assess the combination therapy.
- Administered agonistic CD40 antibody therapy alone and in combination with IL-1R1 blockade.
- Evaluated immune activation, survival rates, and liver toxicity.
Main Results:
- Agonistic CD40 antibody therapy alone activated the immune system and prolonged survival in PDAC-bearing mice.
- The combination therapy upregulated immune-related pathways and enhanced innate and adaptive immune responses.
- However, combining IL-1R1 blockade with CD40 agonistic therapy did not improve efficacy or reduce liver toxicity compared to CD40 agonistic therapy alone.
- CD40 agonist efficacy was partially dependent on CD8+ T cells.
Conclusions:
- IL-1 signaling plays a complex role in modulating immune responses within the PDAC tumor microenvironment.
- IL-1R1 blockade, as monotherapy or in combination with CD40 agonistic antibodies, is not recommended for clinical trials in PDAC due to lack of added benefit and potential toxicity.
- Further research is needed to understand the intricate interplay of IL-1 and CD40 signaling in PDAC immunotherapy.
