title: Active immunotherapy combined with blockade of a coinhibitory pathway achieves regression of large tumor masses in cancer-prone mice.
abstract: Vaccines that aim to expand tumor-specific CD8(+) T cells have yielded disappointing results in cancer patients although they showed efficacy in transplantable tumor mouse models. Using a system that more faithfully mimics a progressing cancer and its immunoinhibitory microenvironment, we here show that in transgenic mice, which gradually develop adenocarcinomas due to expression of HPV-16 E7 within their thyroid, a highly immunogenic vaccine expressing E7 only induces low E7-specific CD8(+) T-cell responses, which fail to affect the size of the tumors. In contrast, the same type of vaccine expressing E7 fused to herpes simplex virus (HSV)-1 glycoprotein D (gD), an antagonist of the coinhibitory B- and T-lymphocyte attenuator (BTLA)/CD160-herpes virus entry mediator (HVEM) pathways, stimulates potent E7-specific CD8(+) T-cell responses, which can be augmented by repeated vaccination, resulting in initial regression of even large tumor masses in all mice with sustained regression in more than half of them. These results indicate that active immunization concomitantly with blockade of the immunoinhibitory HVEM-BTLA/CD160 pathways through HSV-1 gD may result in sustained tumor regression.
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Marcio O
authors.initials: MO
authors.lastname: Lasaro
authors.forename: Marina
authors.initials: M
authors.lastname: Sazanovich
authors.forename: Wynetta
authors.initials: W
authors.lastname: Giles-Davis
authors.forename: Paulus
authors.initials: P
authors.lastname: Mrass
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Bunte
authors.forename: Duane A
authors.initials: DA
authors.lastname: Sewell
authors.forename: S Farzana
authors.initials: SF
authors.lastname: Hussain
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weninger
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Paterson
authors.forename: Hildegund Cj
authors.initials: HC
authors.lastname: Ertl
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology*; D005786:Gene Expression Regulation; D016233:Immunotherapy, Active / Q000379:methods*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013961:Thyroid Gland / Q000276:immunology; D014611:Vaccination / Q000379:methods
chemical_list: C488868:BTLA protein, mouse; D015415:Biomarkers; D019496:Cancer Vaccines; D050725:Papillomavirus E7 Proteins; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506029:Tnfrsf14 protein, mouse; C059731:oncogene protein E7, Human papillomavirus type 16