Targeting Tumor-Associated Fibroblasts Improves Cancer Chemotherapy by Increasing Intratumoral Drug Uptake

J Clin Invest. 2006 Jul;116(7):1955-62. doi: 10.1172/JCI26532. Epub 2006 Jun 22.

Abstract

Tumor-associated fibroblasts are key regulators of tumorigenesis. In contrast to tumor cells, which are genetically unstable and mutate frequently, the presence of genetically more stable fibroblasts in the tumor-stromal compartment makes them an optimal target for cancer immunotherapy. These cells are also the primary source of collagen type I, which contributes to decreased chemotherapeutic drug uptake in tumors and plays a significant role in regulating tumor sensitivity to a variety of chemotherapies. To specifically kill tumor-associated fibroblasts, we constructed an oral DNA vaccine targeting fibroblast activation protein (FAP), which is specifically overexpressed by fibroblasts in the tumor stroma. Through CD8+ T cell-mediated killing of tumor-associated fibroblasts, our vaccine successfully suppressed primary tumor cell growth and metastasis of multidrug-resistant murine colon and breast carcinoma. Furthermore, tumor tissue of FAP-vaccinated mice revealed markedly decreased collagen type I expression and up to 70% greater uptake of chemotherapeutic drugs. Most importantly, pFap-vaccinated mice treated with chemotherapy showed a 3-fold prolongation in lifespan and marked suppression of tumor growth, with 50% of the animals completely rejecting a tumor cell challenge. This strategy opens a new venue for the combination of immuno- and chemotherapies.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines*
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Female
  • Fibroblasts / metabolism*
  • Gelatinases / genetics
  • Gelatinases / metabolism*
  • Gelatinases / therapeutic use
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Membrane Proteins / therapeutic use
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms* / metabolism
  • Neoplasms* / pathology
  • Neoplasms* / therapy
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Recombinant Fusion Proteins / therapeutic use
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Serine Endopeptidases / therapeutic use
  • Survival Rate
  • Vaccines, DNA*

Substances

  • Cancer Vaccines
  • Collagen Type I
  • Membrane Proteins
  • Recombinant Fusion Proteins
  • Vaccines, DNA
  • Serine Endopeptidases
  • fibroblast activation protein alpha
  • Gelatinases