title: Enhanced responses to tumor immunization following total body irradiation are time-dependent.
abstract: The development of successful cancer vaccines is contingent on the ability to induce effective and persistent anti-tumor immunity against self-antigens that do not typically elicit immune responses. In this study, we examine the effects of a non-myeloablative dose of total body irradiation on the ability of tumor-naïve mice to respond to DNA vaccines against melanoma. We demonstrate that irradiation followed by lymphocyte infusion results in a dramatic increase in responsiveness to tumor vaccination, with augmentation of T cell responses to tumor antigens and tumor eradication. In irradiated mice, infused CD8(+) T cells expand in an environment that is relatively depleted in regulatory T cells, and this correlates with improved CD8(+) T cell functionality. We also observe an increase in the frequency of dendritic cells displaying an activated phenotype within lymphoid organs in the first 24 hours after irradiation. Intriguingly, both the relative decrease in regulatory T cells and increase in activated dendritic cells correspond with a brief window of augmented responsiveness to immunization. After this 24 hour window, the numbers of dendritic cells decline, as does the ability of mice to respond to immunizations. When immunizations are initiated within the period of augmented dendritic cell activation, mice develop anti-tumor responses that show increased durability as well as magnitude, and this approach leads to improved survival in experiments with mice bearing established tumors as well as in a spontaneous melanoma model. We conclude that irradiation can produce potent immune adjuvant effects independent of its ability to induce tumor ablation, and that the timing of immunization and lymphocyte infusion in the irradiated host are crucial for generating optimal anti-tumor immunity. Clinical strategies using these approaches must therefore optimize such parameters, as the correct timing of infusion and vaccination may mean the difference between an ineffective treatment and successful tumor eradication.
authors.affiliation: Swim Across America Laboratory of Tumor Immunology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America.
authors.forename: Adi
authors.initials: A
authors.lastname: Diab
authors.affiliation: Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Jenq
authors.affiliation: Swim Across America Laboratory of Tumor Immunology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America ; Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Gabrielle A
authors.initials: GA
authors.lastname: Rizzuto
authors.affiliation: Swim Across America Laboratory of Tumor Immunology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Cohen
authors.affiliation: Swim Across America Laboratory of Tumor Immunology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: Deonka W
authors.initials: DW
authors.lastname: Huggins
authors.affiliation: Swim Across America Laboratory of Tumor Immunology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: Taha
authors.initials: T
authors.lastname: Merghoub
authors.affiliation: Swim Across America Laboratory of Tumor Immunology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: Manuel E
authors.initials: ME
authors.lastname: Engelhorn
authors.affiliation: Swim Across America Laboratory of Tumor Immunology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: José A
authors.initials: JA
authors.lastname: Guevara-Patiño
authors.affiliation: Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Suh
authors.affiliation: Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hubbard-Lucey
authors.affiliation: Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Kochman
authors.affiliation: Susan Lehman Cullman Laboratory for Cancer Research, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey Piscataway, New Brunswick, New Jersey, United States of America.
authors.forename: Suzie
authors.initials: S
authors.lastname: Chen
authors.affiliation: Swim Across America Laboratory of Tumor Immunology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Swim Across America Laboratory of Tumor Immunology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America ; Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America ; Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
authors.affiliation: Swim Across America Laboratory of Tumor Immunology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Immunology Program, Sloan-Kettering Institute, New York, New York, United States of America ; Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
authors.affiliation: Adult Bone Marrow Transplantation Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America ; Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Miguel-Angel
authors.initials: MA
authors.lastname: Perales
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007114:Immunization; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology; D008546:Melanoma, Experimental; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D037182:T-Cell Antigen Receptor Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D019444:Vaccines, DNA / Q000276:immunology; D014916:Whole-Body Irradiation
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D019496:Cancer Vaccines; D019444:Vaccines, DNA; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase