title: Enhancement of fibroblast activation protein α-based vaccines and adenovirus boost immunity by cyclophosphamide through inhibiting IL-10 expression in 4T1 tumor bearing mice.
abstract: Fibroblast activation protein α (FAPα) is expressed in cancer-associated fibroblasts (CAFs) of more than 90% of malignant epithelia carcinomas. CAFs are the main type of cells in the tumor microenvironment which offer nutrition and protection to the tumor and regulate immunosuppression. To eliminate CAFs, a vaccine targeting FAPα may be used with a heterologous prime-boost strategy to enhance the FAPα-specific cellular immunity. Here, a FAP vaccine using a recombinant adenovirus (rAd) vector was constructed as well as a DNA vaccine reported in our previous work. Although the DNA prime-rAd boost strategy enhanced FAPα-specific immune responses, improvement of anti-tumor immunity effects was not observed. Examination of immunosuppressive factors revealed that high expression of the IL-10 cytokine was considered the main cause of the failure of the prime-boost strategy. However, heterologous vaccination in combination with a low-dose of cyclophosphamide (CY), which was reported to reduce IL-10 production and promote a shift from immunosuppression to immunopotentiation, resulted in enhanced effects in terms of numbers of effector T cells and tumor growth inhibition rates, compared to the CY alone or DNA alone group. Tumor growth was inhibited markedly when the prime-boost strategy was combined with CY in both the prophylactic and therapeutic settings and the survival time of 4T1 tumor bearing mice was also prolonged significantly. With the reduction of IL-10, enhancement of the anti-tumor effect by the prime-boost strategy was observed. These results suggest that FAPα-targeted rAd boosting in combination with CY is an attractive approach to overcoming immunosuppression in cancer vaccines.
authors: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors: Qiu
authors: Q
authors: Xia
authors: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors: Fei
authors: F
authors: Geng
authors: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors: Fang-Fang
authors: FF
authors: Zhang
authors: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors: Chen-Lu
authors: CL
authors: Liu
authors: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors: Ping
authors: P
authors: Xu
authors: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors: Zhen-Zhen
authors: ZZ
authors: Lu
authors: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China. Electronic address: Zhanghh@jlu.edu.cn.
authors: Hai-Hong
authors: HH
authors: Zhang
authors: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors: Wei
authors: W
authors: Kong
authors: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors: Xiang-Hui
authors: XH
authors: Yu
mesh_terms: D000256:Adenoviridae; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000494:pharmacology*; D010450:Endopeptidases; D005260:Female; D005347:Fibroblasts / Q000276:immunology; D018093:Gelatinases / Q000276:immunology*; D005822:Genetic Vectors; D007111:Immunity, Cellular; D007117:Immunization, Secondary; D016753:Interleukin-10 / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000628:therapy*; D012697:Serine Endopeptidases / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D059016:Tumor Microenvironment; D019444:Vaccines, DNA / Q000276:immunology; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D019496:Cancer Vaccines; D003520:Cyclophosphamide; D010450:Endopeptidases; D018093:Gelatinases; D016753:Interleukin-10; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D019444:Vaccines, DNA; D000099167:Fibroblast Activation Protein Alpha
keywords: Cancer vaccine; Cyclophosphamide; Fibroblast activation protein α; Immunosuppression; Interleukin-10; Prime-boost strategy