title: The effect of adjuvanting cancer vaccines with herpes simplex virus glycoprotein D on melanoma-driven CD8+ T cell exhaustion.
abstract: Two vaccines expressing CD4(+) and CD8(+) T cell epitopes of melanoma-associated Ags (MAAs) by a chimpanzee-derived replication-defective AdC68 vector were compared in a mouse model of melanoma. In one vaccine, termed AdC68-gDMelapoly, the epitopes were expressed as a fusion protein within HSV-1 glycoprotein D (gD), which blocks immunoinhibitory signaling through the herpes virus entry mediator pathway. The other vaccine, termed AdC68-Melapoly, expressed only the MAA epitopes. AdC68-gDMelapoly induced more potent MAA-specific CD8(+) T cell responses especially to the subdominant MAA epitopes. Upon prophylactic vaccination, mice that developed CD8(+) T cell responses to the two vaccines that were comparable in magnitude showed equal protection against tumor challenge. When mice were first challenged with tumor cells and then vaccinated results differed. In animals with comparable CD8(+) T cell responses, the AdC68-gDMelapoly vaccine was more efficacious compared with the AdC68-Melapoly vaccine in delaying tumor growth. This effect was linked to reduced expression of 2B4, LAG-3, and programmed death-1 on tumor-infiltrating MAA-specific CD8(+) T cells elicited by the gD-adjuvanted vaccine, suggesting that CD8(+) T cells induced in presence of gD are less susceptible to tumor-driven exhaustion.
authors.affiliation: Gene Therapy and Vaccines Program, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Gene Therapy and Vaccines Program, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and Wistar Institute Vaccine Center, University of Pennsylvania, Philadelphia, PA 19104 ertl@wistar.upenn.edu.
authors.forename: Hildegund C J
authors.initials: HC
authors.lastname: Ertl
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D000951:Antigens, Neoplasm / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology*; D002460:Cell Line; D017024:Chemotherapy, Adjuvant; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006389:Hemagglutinins, Viral / Q000235:genetics / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008545:Melanoma / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000096:biosynthesis; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D000071176:Signaling Lymphocytic Activation Molecule Family; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; C490007:Cd244a protein, mouse; D018984:Epitopes, T-Lymphocyte; D006389:Hemagglutinins, Viral; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D000071176:Signaling Lymphocytic Activation Molecule Family; D014759:Viral Envelope Proteins; C039447:glycoprotein D, Human herpesvirus 1; D000093322:Lymphocyte Activation Gene 3 Protein