Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model.

Abstract

Unlike heterogeneous tumor cells, cancer-associated fibroblasts (CAF) are genetically more stable which serve as a reliable target for tumor immunotherapy. Fibroblast activation protein (FAP) which is restrictively expressed in tumor cells and CAF in vivo and plays a prominent role in tumor initiation, progression, and metastasis can function as a tumor rejection antigen. In the current study, we have constructed artificial FAP(+) stromal cells which mimicked the FAP(+) CAF in vivo. We immunized a breast cancer mouse model with FAP(+) stromal cells to perform immunotherapy against FAP(+) cells in the tumor microenvironment. By forced expression of FAP, we have obtained FAP(+) stromal cells whose phenotype was CD11b(+)/CD34(+)/Sca-1(+)/FSP-1(+)/MHC class I(+). Interestingly, proliferation capacity of the fibroblasts was significantly enhanced by FAP. In the breast cancer-bearing mouse model, vaccination with FAP(+) stromal cells has significantly inhibited the growth of allograft tumor and reduced lung metastasis indeed. Depletion of T cell assays has suggested that both CD4(+) and CD8(+) T cells were involved in the tumor cytotoxic immune response. Furthermore, tumor tissue from FAP-immunized mice revealed that targeting FAP(+) CAF has induced apoptosis and decreased collagen type I and CD31 expression in the tumor microenvironment. These results implicated that immunization with FAP(+) stromal cells led to the disruption of the tumor microenvironment. Our study may provide a novel strategy for immunotherapy of a broad range of cancer.

• Authors: Mingyao Meng, Wenju Wang, Jun Yan, Jing Tan, Liwei Liao, Jianlin Shi, Chuanyu Wei, Yanhua Xie, Xingfang Jin, Li Yang, Qing Jin, Huirong Zhu, Weiwei Tan, Fang Yang, Zongliu Hou
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 37 Issue 8 Pg. 10317-27 (Aug 2016) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 26842926 (Publication Type: Journal Article)

Chemical References

• Membrane Proteins
• Endopeptidases
• Serine Endopeptidases
• fibroblast activation protein alpha
• Gelatinases

Topics

• Animals
• Blotting, Western
• Breast Neoplasms (immunology, pathology)
• Disease Models, Animal
• Endopeptidases
• Female
• Fibroblasts (immunology)
• Fluorescent Antibody Technique
• Gelatinases (immunology)
• Immunization
• Immunohistochemistry
• Immunotherapy (methods)
• Membrane Proteins (immunology)
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Serine Endopeptidases (immunology)
• Tumor Microenvironment (immunology)