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  • br Fei Geng Jie Guo Qian Qian Guo Yu

    2019-10-01


    Fei Geng, Jie Guo, Qian-Qian Guo, Yu Xie, Ling Dong, Yi Zhou, Chen-Lu Liu, Bin Yu, Hui Wu, Jia-Xin Wu, Hai-Hong Zhang ⇑, Wei Kong ⇑, Xiang-Hui Yu ⇑ National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China
    Article history:
    Keywords:
    FAPa
    Cancer-associated fibroblast
    Tumour microenvironment
    Myeloid-derived suppressor cell
    DNA vaccine
    Cancer immunotherapy 
    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 FAPa, which is highly expressed by CAFs, to target these CORM-3 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 FAPa-targeted vaccine containing only the extracellular domain of human FAPa 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, lead-ing 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 facil-itate 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 eval-uating the vaccine distribution in the human body. These results indicated that the new FAPa-targeted vaccine expressing an optimized secreted human FAPa induced enhanced anti-tumor activity by reduc-ing the number of FAPa+ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.
    2019 Elsevier Ltd. All rights reserved.
    1. Introduction
    The tumor microenvironment (TME), which includes soluble factors, immune cells, endothelial cells, and cancer-associated fibroblasts (CAFs), plays important roles in tumorigenesis, inva-sion, and metastasis [1,2]. The TME not only provides nutrients for the growth of malignant tumor cells but also protects malig-nant tumor cells from the immune system by disrupting anti-
    Abbreviations: CAFs, Cancer-associated fibroblasts; TME, Tumor microenviron-ment; FAPa, Fibroblast activation protein a; 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; VEGFa, Vascular endothelial growth factor alpha; PDGF, Platelet-derived growth factor; qRT-PCR, Quantitative real time polymerase chain reaction; tPA, Tissue plasminogen activator.
    ⇑ Corresponding authors at: No. 2699, Street Qianjin, School of Life Science, Jilin University, Changchun 130012, PR China.
    tumor immune responses, while supporting those that are immunosuppressive [3,4]. It is noteworthy that the largest propor-tion of soluble factors related to tumor growth are secreted by stro-mal cells rather than malignant tumor cells themselves [5]. Therefore, targeting the TME for the treatment of malignant tumors has been extensively explored [3,6–8].
    CAFs, as major components of tumor stromal cells surrounding the outer layer of tumor cells, promote tumor initiation, invasion, and metastasis via direct cellular interactions, stromal factors, or remodeling the extracellular matrix (ECM) [9–11]. These cells can recruit immunosuppressive cells, such as myeloid-derived sup-pressor cells (MDSCs), which have a remarkable ability to suppress T-cell responses [12], by secreting CCL2 and SDF-1 (CXCL12) into the TME [13–16]. ECM proteins, such as collagen I, secreted by CAFs are distributed around tumor cells to form a barrier that pre-vents chemotherapy drugs from entering the TEM and protects tumor cells from immune attack. Moreover, CAFs are genetically