title: Improvement of anti-tumor immunity of fibroblast activation protein α based vaccines by combination with cyclophosphamide in a murine model of breast cancer.
abstract: Fibroblast activation protein α (FAPα) is expressed in cancer-associated fibroblasts (CAFs), which are the main type of cells in the tumor microenvironment. CAFs exert immunosuppressive activity, which can weaken the effects of cancer immunotherapy and mainly account for poor outcomes with therapeutic vaccines. To better target and destroy CAFs, a FAPα vaccine using a modified vaccinia ankara (MVA) vector was constructed and used with a DNA vaccine reported in our previous work for heterologous prime-boost immunizations in mice. This strategy to generate anti-tumor immunity partly reduced 4T1 tumor growth through producing FAPα-specific cytotoxic T lymphocyte responses in a preventive model, but the effect required improvement. Combining the FAPα-based cancer vaccines (CpVR-FAP/MVA-FAP) with cyclophosphamide (CY), which can be used not only as a chemotherapeutic but also an immunomodulatory agent to promote a shift from immunosuppression to immunopotentiation, resulted in markedly enhanced tumor growth inhibition compared with the CpVR-FAP/MVA-FAP group. This strategy achieved synergistic effects in a therapeutic model by improving the tumor inhibition rate by 2.5-fold (90.2%), significantly enhancing cellular immunity and prolonging the survival of 4T1 tumor-bearing mice by 35% compared with the PBS group. Furthermore, CAFs, stromal factors and immunosuppressive factors such as IL-10 and Tregs were also markedly decreased by the CY combination. These results indicated that FAPα-targeted MVA boosting in combination with CY is an effective approach to improving specific anti-tumor immune responses through overcoming immunosuppression. This study may offer important advances in research on clinical cancer immunotherapies by modulating immunosuppressive factors.
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Qiu
authors.initials: Q
authors.lastname: Xia
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Zhang
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Fei
authors.initials: F
authors.lastname: Geng
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Chen-Lu
authors.initials: CL
authors.lastname: Liu
authors.affiliation: China-Japan Union Hospital of Jilin University, Scientific Research Center, Changchun 130012, PR China.
authors.forename: Yu-Qian
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Ping
authors.initials: P
authors.lastname: Xu
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Zhen-Zhen
authors.initials: ZZ
authors.lastname: Lu
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Xie
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wu
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Kong
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China.
authors.forename: Xiang-Hui
authors.initials: XH
authors.lastname: Yu
authors.affiliation: National Engineering Laboratory for AIDS Vaccine, School of Life Science, Jilin University, Changchun 130012, PR China. Electronic address: Zhanghh@jlu.edu.cn.
authors.forename: Hai-Hong
authors.initials: HH
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004195:Disease Models, Animal; D010450:Endopeptidases; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D018093:Gelatinases / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors; D007117:Immunization, Secondary; D007155:Immunologic Factors / Q000627:therapeutic use*; D007167:Immunotherapy / Q000379:methods*; D016753:Interleukin-10 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D012697:Serine Endopeptidases / Q000235:genetics / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D059016:Tumor Microenvironment; D019444:Vaccines, DNA; D014615:Vaccinia / Q000235:genetics; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D019496:Cancer Vaccines; D003520:Cyclophosphamide; D010450:Endopeptidases; D018093:Gelatinases; D007155:Immunologic Factors; 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; Prime-boost strategy