Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model

Cancer Immunol Immunother. 2016 May;65(5):613-24. doi: 10.1007/s00262-016-1827-4. Epub 2016 Mar 28.

Abstract

Fibroblast activation protein α (FAPα) is a tumor stromal antigen overexpressed by cancer-associated fibroblasts (CAFs). CAFs are genetically more stable compared with the tumor cells and immunosuppressive components of the tumor microenvironment, rendering them excellent targets for cancer immunotherapy. DNA vaccines are widely applied due to their safety. To specifically destroy CAFs, we constructed and examined the immunogenicity and anti-tumor immune mechanism of a DNA vaccine expressing human FAPα. This vaccine successfully reduced 4T1 tumor growth through producing FAPα-specific cytotoxic T lymphocyte responses which could kill CAFs, and the decrease in FAPα-expressing CAFs resulted in markedly attenuated expression of collagen I and other stromal factors that benefit the tumor progression. Based on these results, a DNA vaccine targeting human FAPα may be an attractive and effective cancer immunotherapy strategy.

Keywords: CAF; DNA vaccine; FAPα; Immune suppression; Immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cancer Vaccines / immunology*
  • Cancer Vaccines / pharmacology
  • Cell Line, Tumor
  • Collagen Type I / immunology
  • Collagen Type I / metabolism
  • Endopeptidases
  • Female
  • Fibroblasts / drug effects
  • Fibroblasts / immunology
  • Fibroblasts / metabolism
  • Gelatinases / genetics
  • Gelatinases / immunology*
  • Gelatinases / metabolism
  • Humans
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / immunology*
  • Mammary Neoplasms, Experimental / pathology
  • Membrane Proteins / genetics
  • Membrane Proteins / immunology*
  • Membrane Proteins / metabolism
  • Mice, Inbred BALB C
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / immunology*
  • Serine Endopeptidases / metabolism
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Burden / drug effects
  • Tumor Burden / immunology
  • Tumor Microenvironment / drug effects
  • Tumor Microenvironment / immunology*
  • Vaccination / methods
  • Vaccines, DNA / immunology*
  • Vaccines, DNA / pharmacology

Substances

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