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.

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