Vaccine against gastrin, a polyclonal antibody stimulator, decreases pancreatic cancer metastases.

Abstract

Growth of pancreatic cancer is stimulated by gastrin in both a paracrine and an autocrine fashion. Traditional therapies have not significantly improved survival, and recently pancreatic cancer has been deemed a "cold" tumor due to its poor response to immunotherapy. Strategies to improve survival of pancreatic cancer are desperately needed. In the current investigation, we studied the effects of an anti-gastrin cancer vaccine, polyclonal antibody stimulator (PAS; formerly called G17DT and Gastrimmune), used alone or in combination with a programmed cell death receptor (PD)-1 immune checkpoint antibody on pancreatic cancer growth, metastases, and the tumor microenvironment (TME). Immune-competent female C57BL/6 mice bearing syngeneic orthotopic murine pancreatic cancer treated with PAS had significantly smaller tumors and fewer metastases. Examination of the TME demonstrated decreased fibrosis with fewer M2 and more M1 tumor-associated macrophages. Expression of the E-cadherin gene was significantly increased and expression of the TGFβR2 gene was decreased compared with controls. Mice treated with PAS or the combination of PAS and PD-1 antibody exhibited significantly less tumor expression of phospho-paxillin, the focal adhesion protein β-catenin, and matrix metalloproteinase-7. This study suggests that inhibition of the cancer-promoting effects of gastrin in pancreatic cancer can decrease metastases by altering the TME and decreasing pathways that activate the epithelial mesenchymal transition. The PAS vaccine appears to change the TME, making it more susceptible to therapy with an immune checkpoint antibody. This novel combination of two immunotherapies may improve survival of pancreatic cancer by decreasing both tumor growth and metastasis formation.NEW & NOTEWORTHY Survival from advanced pancreatic cancer is poor, in part due to dense fibrosis of the tumor microenvironment, increased number of M2-polarized macrophages that promote angiogenesis and invasion, and lack of "target-specific" therapy. Herein, we report that a tumor vaccine that selectively targets gastrin decreases pancreatic cancer growth and metastases. Furthermore, the gastrin vaccine polyclonal antibody stimulator alters the tumor microenvironment rendering it more responsive to immunotherapy with a programmed cell death receptor-1 immune checkpoint antibody.

• Authors: Nicholas Osborne, Rebecca Sundseth, Martha D Gay, Hong Cao, Robin D Tucker, Sandeep Nadella, Shangzi Wang, Xunxian Liu, Alexander Kroemer, Lynda Sutton, Allen Cato, Jill P Smith
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 317 Issue 5 Pg. G682-G693 (11 01 2019) ISSN: 1522-1547 [Electronic] United States
• PMID: 31433212 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Cancer Vaccines
• Gastrins
• Programmed Cell Death 1 Receptor
• beta Catenin
• gastrin immunogen
• Receptor, Transforming Growth Factor-beta Type II
• Matrix Metalloproteinase 7

Topics

• Animals
• Cadherins (genetics, metabolism)
• Cancer Vaccines (immunology, therapeutic use)
• Cell Line
• Cell Line, Tumor
• Female
• Gastrins (immunology, therapeutic use)
• Immunotherapy (methods)
• Macrophages (metabolism)
• Matrix Metalloproteinase 7 (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Neoplasm Metastasis
• Pancreatic Neoplasms (pathology, therapy)
• Programmed Cell Death 1 Receptor (genetics, metabolism)
• Receptor, Transforming Growth Factor-beta Type II (genetics, metabolism)
• Tumor Microenvironment
• beta Catenin (genetics, metabolism)