Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model

Cancer Sci. 2010 Nov;101(11):2325-32. doi: 10.1111/j.1349-7006.2010.01695.x.

Abstract

Murine studies have shown that immunological targeting of fibroblast activation protein (FAP) can elicit protective immunity in the absence of significant pathology. Fibroblast activation protein is a product overexpressed by tumor-associated fibroblasts (TAF) and is the predominant component of the stoma in most types of cancer. Tumor-associated fibroblasts differ from normal adult tissue fibroblasts, and instead resemble transient fetal and wound healing-associated fibroblasts. Tumor-associated fibroblasts are critical regulators of tumorigenesis, but differ from tumor cells by being more genetically stable. Therefore, in comparison to tumor cells, TAF may represent more viable therapeutic targets for cancer immunotherapy. To specifically target TAF, we constructed a DNA vaccine directed against FAP. This vaccine significantly suppressed primary tumor and pulmonary metastases primarily through CD8(+) T-cell-mediated killing in tumor-bearing mice. Most importantly, tumor-bearing mice vaccinated against FAP exhibited a 1.5-fold increase in lifespan and no significant pathology. These results suggest that FAP, a product preferentially expressed by TAF, could function as an effective tumor rejection antigen.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / genetics
  • Cancer Vaccines / immunology
  • Cell Line, Tumor
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / therapy*
  • Disease Models, Animal
  • Female
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Gelatinases / genetics
  • Gelatinases / immunology*
  • Gelatinases / metabolism
  • Humans
  • Immunization / methods
  • Immunohistochemistry
  • Immunotherapy / methods*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / prevention & control
  • Lung Neoplasms / secondary
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / immunology*
  • Serine Endopeptidases / metabolism
  • Survival Analysis
  • Tumor Burden / immunology
  • Vaccines, DNA / genetics
  • Vaccines, DNA / immunology*

Substances

  • Cancer Vaccines
  • Membrane Proteins
  • Vaccines, DNA
  • Serine Endopeptidases
  • fibroblast activation protein alpha
  • Gelatinases