title: Soluble B and T lymphocyte attenuator possesses antitumor effects and facilitates heat shock protein 70 vaccine-triggered antitumor immunity against a murine TC-1 cervical cancer model in vivo.
abstract: B and T lymphocyte attenuator (BTLA)-herpesvirus entry mediator (HVEM) signaling coinhibitory pathway is believed to impair antitumor immune competences. An intriguing unresolved question is whether blockade of BTLA-HVEM guides an effective therapeutic tool against established tumors. To address this issue, we constructed a eukaryotic expression plasmid (psBTLA) that expressed the extracellular domain of murine BTLA (soluble form of BTLA), which could bind HVEM, the ligand of BTLA, and block BTLA-HVEM interactions. The data in this study showed that treatment by injection of psBTLA resulted in down-regulation of IL-10 and TGF-beta and promotion of dendritic cell function by increasing the expression of B7-1 and IL-12, but the adaptive antitumor immune responses achieved by psBTLA administration alone were limited and could not eradicate the tumor effectively. Next, we evaluated the immunotherapeutic efficacy and mechanism of combination therapy of heat shock protein 70 (HSP70) vaccine/psBTLA by using murine TC-1 cervical cancer mice as an ectopic tumor model. Our in vivo studies revealed that treatment with HSP70 vaccine alone did not lead to satisfactory tumor growth inhibition, whereas cotreatment with psBTLA significantly improved antitumor immunity and compensated the deficiency of HSP70 vaccine by increasing the expression of Th1 cytokines, IL-2, and IFN-gamma and decreasing transcription levels of IL-10, TGF-beta, and Foxp3 in the tumor microenvironment. Taken together, our findings indicate that blocking the BTLA-HVEM interaction with sBTLA enhances antitumor efficacy and results in a significant synergistic effect against existent tumor cells in vivo when combined with the HSP70 vaccine.
authors.affiliation: Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
authors.forename: Lingfei
authors.initials: L
authors.lastname: Han
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Fang
authors.forename: Zuohua
authors.initials: Z
authors.lastname: Feng
authors.forename: Shujie
authors.initials: S
authors.lastname: Liao
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Li
authors.forename: Mayinuer
authors.initials: M
authors.lastname: Maitituoheti
authors.forename: Hong
authors.initials: H
authors.lastname: Dong
authors.forename: Zhiwen
authors.initials: Z
authors.lastname: Lai
authors.forename: Qinglei
authors.initials: Q
authors.lastname: Gao
authors.forename: Ling
authors.initials: L
authors.lastname: Xi
authors.forename: Mingfu
authors.initials: M
authors.lastname: Wu
authors.forename: Daowen
authors.initials: D
authors.lastname: Wang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Zhou
authors.forename: Li
authors.initials: L
authors.lastname: Meng
authors.forename: Shixuan
authors.initials: S
authors.lastname: Wang
authors.forename: Ding
authors.initials: D
authors.lastname: Ma
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005110:Extracellular Space / Q000276:immunology / Q000378:metabolism; D005260:Female; D018840:HSP70 Heat-Shock Proteins / Q000008:administration & dosage / Q000276:immunology*; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D017434:Protein Structure, Tertiary; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
chemical_list: C488868:BTLA protein, mouse; D018840:HSP70 Heat-Shock Proteins; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506029:Tnfrsf14 protein, mouse; D019444:Vaccines, DNA