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Updated: Aug 5, 2026
Immunophenotyping of Orthotopic Homograft Syngeneic of Murine Primary KPC Pancreatic Ductal Adenocarcinoma by Flow Cytometry
Published on: October 9, 2018
A Combinatorial Effect of Immune Checkpoint Inhibitors and CD40 Agonistic Antibody in Murine Pancreatic Cancer Model
Juri Ichikawa1, Hiroshi Okuda1, Kuniyuki Kawano1,2
1Department of Immunology, Yokohama City University Graduate School of Medicine, Kanagawa, Japan.
Abstract:
Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses of all cancer types. Immune checkpoint inhibitors (ICIs) are currently not indicated for patients with PDAC except for those with high microsatellite instability. In this study, we developed an immunocompetent orthotopic transplant mouse model with Kras and Trp53 mutations, characterized by high fibrosis and an immunosuppressive tumor microenvironment, closely mimicking human PDAC lesions. This model provides a robust platform for investigating strategies for improving ICI efficacy. We observed that ICI monotherapy yielded minimal efficacy, whereas anti-CD40 agonist antibody (aCD40) monotherapy prolonged survival despite its low impact on primary tumor volume. Moreover, ICIs + aCD40 combination therapy not only extended survival but also significantly reduced tumor burden. These effects were accompanied by enhanced dendritic cell migration to the lymph nodes and T cell priming and activation. Moreover, the expression of immunosuppressive markers in tumor-associated macrophages was decreased. Indeed, gene expression analyses of infiltrating immune cells have revealed a shift in the tumor microenvironment from an immune-tolerant state to an immune-activated state. Our findings suggest that combination therapy with ICIs and aCD40 is a promising treatment strategy for patients with PDAC.
Insights
Combination therapy using immune checkpoint inhibitors (ICIs) and anti-CD40 agonist antibody (aCD40) shows promise for pancreatic cancer. This approach enhances anti-tumor immunity and reduces tumor burden in preclinical models.
Area of Science:
- Oncology
- Immunology
- Cancer Research
Background:
- Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with limited treatment options.
- Immune checkpoint inhibitors (ICIs) are ineffective for most PDAC patients.
- Developing effective immunotherapies for PDAC requires suitable preclinical models.
Purpose of the Study:
- To develop and validate an immunocompetent mouse model of PDAC.
- To investigate the efficacy of ICI monotherapy, anti-CD40 agonist antibody (aCD40) monotherapy, and combination therapy.
- To elucidate the immunological mechanisms underlying treatment responses.
Main Methods:
- Development of an immunocompetent orthotopic transplant mouse model with Kras and Trp53 mutations.
- Treatment of mice with ICIs, aCD40, or combination therapy.
- Assessment of tumor burden, survival, immune cell infiltration, and gene expression.
Main Results:
- ICI monotherapy showed minimal efficacy.
- aCD40 monotherapy prolonged survival but had limited impact on primary tumor volume.
- Combination therapy significantly reduced tumor burden and extended survival.
- Combination therapy enhanced dendritic cell migration, T cell activation, and shifted the tumor microenvironment to an immune-activated state.
- Immunosuppressive markers in tumor-associated macrophages were decreased.
Conclusions:
- The developed mouse model closely mimics human PDAC, featuring high fibrosis and an immunosuppressive tumor microenvironment.
- Combination therapy with ICIs and aCD40 is a promising strategy for PDAC treatment.
- This combination therapy effectively overcomes tumor-induced immunosuppression and enhances anti-tumor immunity.
