A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer. Issue 31 (18th July 2019)

• Record Type: Journal Article
• Authors: Geng, Fei; Guo, Jie; Guo, Qian-Qian; Xie, Yu; Dong, Ling; Zhou, Yi; Liu, Chen-Lu; Yu, Bin; Wu, Hui; Wu, Jia-Xin; Zhang, Hai-Hong; Kong, Wei; Yu, Xiang-Hui
• Is Part Of: Vaccine. Volume 37:Issue 31(2019)
• Page Start: 4382
• Page End: 4391
• Publication Date: 2019-07-18
• Subjects: FAPα -- Cancer-associated fibroblast -- Tumour microenvironment -- Myeloid-derived suppressor cell -- DNA vaccine -- Cancer immunotherapy; CAFs Cancer-associated fibroblasts -- TME Tumor microenvironment -- FAPα Fibroblast activation protein α -- SDF-1 Stromal cell-derived factor-1 -- Th1 T helper type 1 -- Th2 T helper type 2 -- Tregs Regulatory T cells -- MDSCs Myeloid-derived suppressor cells -- VEGFα Vascular endothelial growth factor alpha -- PDGF Platelet-derived growth factor -- qRT-PCR Quantitative real time polymerase chain reaction -- tPA Tissue plasminogen activator; Vaccines -- Periodicals; 615.372
• DOI: 10.1016/j.vaccine.2019.06.012
• Languages: English
• ISSNs: 0264-410X

Abstract

Highlights: An optimized FAPα-targeted DNA vaccine was constructed. DNA sequence homology between optimized FAPα and original FAPα was only 76%. The vaccine induced more FAPα-specific CD8 + T cells. Clearance of CAFs decreased the infiltration of MDSCs in tumor. Mouse FAPα vaccine and human FAPα vaccine had similar anti-tumor effects. Abstract: Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8 + T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα + CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.