Immunization of stromal cell targeting fibroblast activation protein providing immunotherapy to breast cancer mouse model
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.
KeywordsFibroblast activation protein Cancer-associated fibroblast Immunotherapy Tumor microenvironment Breast cancer model
This work is supported by grants from the National Natural Science Foundation of China (nos. 81160267, 81360245, and 81460436) and grants from the “Special and Joint Program” of Yunnan Province Science and Technology Department and Kunming Medical University (nos. 2013FB110 and 2015FA008). This study is also funded by “International Collaboration Program” from Yunnan Province Science and Technology Department (2015IA034).
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Conflicts of interest
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