Novel, genetically induced mouse model that recapitulates the histological morphology and immunosuppressive tumor microenvironment of metastatic peritoneal carcinomatosis

J Immunother Cancer. 2020 Feb;8(1):e000480. doi: 10.1136/jitc-2019-000480.

Abstract

Background: Peritoneal carcinomatosis is a hallmark of advanced peritoneal tumor progression, particularly for tubal/ovarian high-grade serous carcinomas (HGSCs). Patients with peritoneal carcinomatosis have poor survival rates and are difficult to treat clinically due to widespread tumor dissemination in the peritoneal cavity.

Methods: We developed a clinically relevant, genetically induced, peritoneal carcinomatosis model that recapitulates the histological morphology and immunosuppressive state of the tumor microenvironment of metastatic peritoneal HGSCs by intraperitoneally injecting shp53, AKT, c-Myc, luciferase and sleeping beauty transposase, followed by electroporation (EP) in the peritoneal cavity of immunocompetent mice (intraperitoneal (IP)/EP mice).

Results: Similar to the spread of human ovarian cancers, IP/EP mice displayed multiple tumor nodules attached to the surface of the abdomen. Histopathological analysis indicated that these tumors were epithelial in origin. These IP/EP mice also displayed a loss of CD3+ T cell infiltration in tumors, highly expressed inhibitory checkpoint molecules in tumor-infiltrating and global CD4+ and CD8+ T cells, and increased levels of transforming growth factor-β in the ascites, all of which contribute to the promotion of tumor growth.

Conclusions: Overall, our tumor model recapitulates clinical peritoneal HGSC metastasis, which makes it ideal for preclinical drug screening, testing of immunotherapy-based therapeutics and studying of the tumor biology of peritoneal carcinomatosis.

Keywords: immunotherapy; translational medical research; vaccination.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Disease Models, Animal
  • Electroporation
  • Female
  • Humans
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Transgenic
  • Oncogenes / genetics
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / pathology*
  • Peritoneal Neoplasms / genetics*
  • Peritoneal Neoplasms / secondary
  • Primary Cell Culture
  • Transposases / genetics
  • Tumor Escape / genetics*
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology*
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Transposases