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

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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.

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Abbreviations

CAFs:

cancer-associated fibroblasts

CCK:

cholecystokinin

CCKR:

cholecystokinin receptor

CTLA-4:

cytotoxic T–lymphocyte-associated antigen 4

DMEM:

Dulbecco’s Modified Eagle Medium

PanIN:

pancreatic intraepithelial neoplasia

PDAC:

pancreatic ductal adenocarcinoma

PD-1:

programmed cell death protein-1

SCID:

severe combined immune deficiency

α-SMA:

alpha smooth muscle actin

TILs:

tumor-infiltrating lymphocytes

Tregs:

T-regulatory lymphocytes

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Acknowledgements

Grant support: Supported by the National Institutes of Health, National Cancer Institute grants CA50633, and CA194745. These studies were conducted in part at the Lombardi Comprehensive Cancer Center Histopathology & Tissue Shared resource and in the Preclinical Imaging Research Laboratory which is supported in part by NIH/NCI grant P30-CA051008.

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Authors and Affiliations

  1. Department of Medicine, Georgetown University, Building D, Room 338, 4000 Reservoir Rd, Washington DC, NW, 20007, USA

    Jill P. Smith & Sandeep Nadella

  2. Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, USA

    Jill P. Smith, Shangzi Wang, Sandra A. Jablonski & Louis M. Weiner

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  1. Jill P. Smith
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Correspondence to Jill P. Smith.

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Smith, J.P., Wang, S., Nadella, S. et al. Cholecystokinin receptor antagonist alters pancreatic cancer microenvironment and increases efficacy of immune checkpoint antibody therapy in mice. Cancer Immunol Immunother 67, 195–207 (2018). https://doi.org/10.1007/s00262-017-2077-9

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