title: AAV-sBTLA facilitates HSP70 vaccine-triggered prophylactic antitumor immunity against a murine melanoma pulmonary metastasis model in vivo.
abstract: Activation of the BTLA-HVEM co-inhibitory signaling pathway impairs antitumor immunity. Our previous study demonstrated that the extracellular domain of murine BTLA (the soluble form of BTLA) can facilitate HSP70 vaccine-triggered antitumor immunity by blocking BTLA-HVEM interactions in a murine TC-1 non-metastatic tumor model. However, it is unknown whether this strategy has beneficial effects on highly malignant metastatic tumors, such as melanoma. To address this question, we expressed the soluble form of BTLA (sBTLA) in combination with HSP70 vaccine and examined the resulting antitumor activity in a melanoma pulmonary metastasis model. A recombinant adeno-associated virus (AAV) vector was used for the sBTLA gene delivery because of its high transfection efficiency and low toxicity. In vitro expression of AAV-sBTLA enhanced lymphocyte activation and induced specific cytotoxicity against B16F1 murine melanoma cells, while in vivo administration of AAV-sBTLA plus HSP70 vaccine by tail vein injection exerted a limited, late-stage antitumor effect against the existing B16F1 cells. However, the combination treatment generated a potent prophylactic antitumor response in the melanoma lung metastasis model in B6 mice. In this case, most of the metastatic foci were inhibited, and mouse survival was prolonged. Furthermore, the Th1 cytokines IL-2 and IFN-γ were up-regulated, while the negative regulatory molecules IL-10 and TGF-β were down-regulated. The number of regulatory T cells also decreased in the tumor environment. Therefore, AAV-sBTLA plus HSP70 vaccine may have therapeutic potential for the prevention of metastatic melanoma.
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: lingfeihan@hotmail.com.
authors.forename: Lingfei
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Gynecology and Obstetrics, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Neurological and Oncological Sciences, Mount Sinai School of Medicine, New York City, NY 10029, USA.
authors.forename: Jiahong
authors.initials: J
authors.lastname: Lu
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Fanfei
authors.initials: F
authors.lastname: Kong
authors.affiliation: Department of Neurological and Oncological Sciences, Mount Sinai School of Medicine, New York City, NY 10029, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Ma
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jianlong
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Shuai
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Ye
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tao
authors.affiliation: Florida Hospital Gynecologic Oncology, Florida Hospital Cancer Institute and the Global Robotics Institute, Orlando, FL 32804, USA.
authors.forename: Sarfraz
authors.initials: S
authors.lastname: Ahmad
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: 09lifang@tongji.edu.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Minimally Invasive Gynecologic Surgery, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address: sunjing61867@yahoo.com.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
mesh_terms: D000818:Animals; D016466:CHO Cells; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology*; D003412:Cricetulus; D000229:Dependovirus / Q000235:genetics; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology*; D014162:Transfection
chemical_list: C488868:BTLA protein, mouse; D019496:Cancer Vaccines; D018840:HSP70 Heat-Shock Proteins; D011971:Receptors, Immunologic
keywords: AAV; BTLA; HSP70 vaccine; Immunotherapy; Metastatic melanoma