Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice

Abstract

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.

A Cholecystokinin Receptor Antagonist Halts Nonalcoholic Steatohepatitis and Prevents Hepatocellular Carcinoma

“…Apart from their proliferative role on cancer cells, CCK receptors have been identified on pancreatic stellate cells [40] and fibroblasts [41]. Proglumide treatment decreases tumor-associated fibrosis in mouse models of pancreatic cancer [24,36,42]. Although CCK receptors have not been reported on hepatic stellate cells, the liver and pancreas develop from endodermal epithelium of the embryonic foregut [43] and have many common features.…”

Cholecystokinin Receptor-Targeted Polyplex Nanoparticle Inhibits Growth and Metastasis of Pancreatic Cancer

“…We previously showed that if gastrin signaling at the CCK-B receptor was blocked with a CCK-receptor antagonist, that fibrosis and inflammation in the tumor microenvironment is decreased significantly. 9 , 36 in part by interference with the CCK-B receptor on the pancreatic stellate cells or cancer-associated fibroblasts. Therefore, it is not surprising to find that the polyplex carrying gastrin siRNA to tumors also can alter genes associated with tumor fibrosis and inflammation.…”

Neuropeptide G Protein-Coupled Receptors as Oncotargets

“…The GPCR can be used to direct neuropeptide coated nanoparticle to the tumor. Recently, cholecystokinin antagonists were found to potentiate the effects of immune checkpoint inhibitors at impairing the growth of pancreatic tumors in vivo ( 138 ). Thus GPCR antagonists can potentiate the effects of various drugs in cancer treatment.…”