Advanced pancreatic ductal
adenocarcinoma (PDAC) has typically been resistant to
chemotherapy and
immunotherapy; therefore, novel strategies are needed to enhance therapeutic response.
Cholecystokinin (CCK) has been shown to stimulate growth of
pancreatic cancer.
CCK receptors (CCKRs) are present on
pancreatic cancer cells, fibroblasts, and lymphocytes. We hypothesized that CCKR blockade would improve response to immune checkpoint
antibodies by promoting influx of tumor-infiltrating lymphocytes (TILs) and reducing
fibrosis. We examined the effects of CCKR antagonists or
immune checkpoint blockade antibodies alone or in combination in murine models of PDAC. Monotherapy with CCKR blockade significantly decreased
tumor size and
metastases in SCID mice with orthotopic PDAC, and in C57BL/6 mice, it reduced
fibrosis and induced the influx of TILs. Immune-competent mice bearing syngeneic
pancreatic cancer (Panc02 and mT3-2D) that were treated with the combination of
CCK receptor antagonists and
immune checkpoint blockade antibodies survived significantly longer with smaller
tumors.
Tumor immunohistochemical staining and flow cytometry demonstrated that the
tumors of mice treated with the combination regimen had a significant reduction in Foxp3+ T-regulatory cells and an increase in CD4+ and CD8+ lymphocytes. Masson's
trichrome stain analysis revealed 50% less
fibrosis in the
tumors of mice treated with CCKR antagonist compared to controls and compared to checkpoint antibody
therapy. CCKR antagonists given with immune checkpoint antibody
therapy represent a novel approach for improving survival of PDAC. The mechanism by which this combination
therapy improves the survival of PDAC may be related to the decreased
fibrosis and immune cells of the tumor microenvironment.