A whole-cell tumor vaccine modified to express fibroblast activation protein induces antitumor immunity against both tumor cells and cancer-associated fibroblasts.

Abstract

Cancer-associated fibroblasts (CAFs) are common components of the tumor-suppressive microenvironment, and are a major determinant of the poor outcome of therapeutic vaccination. In this study, we modified tumor cells to express the fibroblast activation protein (FAP), which is highly expressed by CAFs, to potentially improve whole-cell tumor vaccines by targeting both tumor cells and CAFs. Tumor cells were transfected with murine FAP plasmids bearing the cationic lipid DOTAP. Its antitumor effects were investigated in three established tumor models. Vaccination with tumor cells expressing FAP eliminated solid tumors and tumors resulting from hematogenous dissemination. This antitumor immune response was mediated by CD8+ T cells. Additionally, we found that CAFs were significantly reduced within the tumors. Furthermore, this vaccine enhanced the infiltration of CD8+ T lymphocytes, and suppressed the accumulation of immunosuppressive cells in the tumor microenvironment. Our results indicated that the FAP-modified whole-cell tumor vaccine induced strong antitumor immunity against both tumor cells and CAFs and reversed the immunosuppressive effects of tumors by decreasing the recruitment of immunosuppressive cells and enhancing the recruitment of effector T cells. This conclusion may have important implications for the clinical use of genetically modified tumor cells as cancer vaccines.

• Authors: Meihua Chen, Rong Xiang, Yuan Wen, Guangchao Xu, Chunting Wang, Shuntao Luo, Tao Yin, Xiawei Wei, Bin Shao, Ning Liu, Fuchun Guo, Meng Li, Shuang Zhang, Minmin Li, Kexing Ren, Yongsheng Wang, Yuquan Wei
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 14421 (Sep 23 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26394925 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Neoplasm
• Antineoplastic Agents
• Cancer Vaccines
• Membrane Proteins
• Endopeptidases
• Serine Endopeptidases
• fibroblast activation protein alpha
• Gelatinases

Topics

• Animals
• Antigens, Neoplasm (immunology)
• Antineoplastic Agents (immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (immunology)
• Carcinoma, Lewis Lung (immunology, therapy)
• Cell Line, Tumor
• Colonic Neoplasms (immunology, therapy)
• Endopeptidases
• Fibroblasts (immunology)
• Gelatinases (biosynthesis, genetics)
• Immunotherapy (methods)
• Melanoma, Experimental (immunology, therapy)
• Membrane Proteins (biosynthesis, genetics)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Serine Endopeptidases (biosynthesis, genetics)
• Tumor Microenvironment (immunology)
• Vaccination