title: Sindbis viral vectors transiently deliver tumor-associated antigens to lymph nodes and elicit diversified antitumor CD8+ T-cell immunity.
abstract: Tumors are theoretically capable of eliciting an antitumor immune response, but are often poorly immunogenic. Oncolytic viruses (OVs) have recently emerged as a promising strategy for the immunogenic delivery of tumor-associated antigens (TAAs) to cancer patients. However, safe and effective OV/TAA therapies have not yet been established. We have previously demonstrated that vectors based on Sindbis virus (SV) can inhibit tumor growth and activate the innate immune system in mice. Here, we demonstrate that SV vectors carrying a TAA generate a dramatically enhanced therapeutic effect in mice bearing subcutaneous, intraperitoneal, and lung cancers. Notably, SV/TAA efficacy was not dependent on tumor cell targeting, but was characterized by the transient expression of TAAs in lymph nodes draining the injection site. Early T-cell activation at this site was followed by a robust influx of NKG2D expressing antigen-specific cytotoxic CD8+ T cells into the tumor site, subsequently leading to the generation of long-lasting memory T cells which conferred protection against rechallenge with TAA-positive as well as TAA-negative tumor cells. By combining in vivo imaging, flow cytometry, cytotoxicity/cytokine assays, and tetramer analysis, we investigated the relationship between these events and propose a model for CD8+ T-cell activation during SV/TAA therapy.
authors.affiliation: Department of Pathology, NYU School of Medicine, NYU Cancer Institute, NYU Gene Therapy Center, New York, New York, USA.
authors.forename: Tomer
authors.initials: T
authors.lastname: Granot
authors.affiliation: Department of Pathology, NYU School of Medicine, NYU Cancer Institute, NYU Gene Therapy Center, New York, New York, USA.
authors.forename: Yoshihide
authors.initials: Y
authors.lastname: Yamanashi
authors.affiliation: Department of Pathology, NYU School of Medicine, NYU Cancer Institute, NYU Gene Therapy Center, New York, New York, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Meruelo
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D006224:Cricetinae; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D007156:Immunologic Memory; D008198:Lymph Nodes / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D050504:Oncolytic Viruses / Q000235:genetics / Q000276:immunology; D012845:Sindbis Virus / Q000235:genetics* / Q000276:immunology; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte
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