title: Immunotherapy-induced CD8+ T cells instigate immune suppression in the tumor.
abstract: Despite clear evidence of immunogenicity, cancer vaccines only provide a modest clinical benefit. To evaluate the mechanisms that limit tumor regression following vaccination, we have investigated the weak efficacy of a highly immunogenic experimental vaccine using a murine melanoma model. We discovered that the tumor adapts rapidly to the immune attack instigated by tumor-specific CD8+ T cells in the first few days following vaccination, resulting in the upregulation of a complex set of biological networks, including multiple immunosuppressive processes. This rapid adaptation acts to prevent sustained local immune attack, despite continued infiltration by increasing numbers of tumor-specific T cells. Combining vaccination with adoptive transfer of tumor-specific T cells produced complete regression of the treated tumors but did not prevent the adaptive immunosuppression. In fact, the adaptive immunosuppressive pathways were more highly induced in regressing tumors, commensurate with the enhanced level of immune attack. Examination of tumor infiltrating T-cell functionality revealed that the adaptive immunosuppression leads to a progressive loss in T-cell function, even in tumors that are regressing. These novel observations that T cells produced by therapeutic intervention can instigate a rapid adaptive immunosuppressive response within the tumor have important implications for clinical implementation of immunotherapies.
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: A J Robert
authors.initials: AJ
authors.lastname: McGray
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Robin
authors.initials: R
authors.lastname: Hallett
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Dannie
authors.initials: D
authors.lastname: Bernard
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Swift
authors.affiliation: Tumor Immunity and Tolerance, Cancer and Inflammation Program, FCRF, CCR, NCI, NIH, Frederick, Maryland, USA.
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Florentina
authors.initials: F
authors.lastname: Teoderascu
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Heather
authors.initials: H
authors.lastname: Vanseggelen
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: John A
authors.initials: JA
authors.lastname: Hassell
authors.affiliation: Tumor Immunity and Tolerance, Cancer and Inflammation Program, FCRF, CCR, NCI, NIH, Frederick, Maryland, USA.
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Hurwitz
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Yonghong
authors.initials: Y
authors.lastname: Wan
authors.affiliation: McMaster Immunology Research Centre, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Bramson
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology; D005260:Female; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D056747:Immunomodulation / Q000235:genetics / Q000276:immunology; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D009364:Neoplasm Recurrence, Local; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics / Q000276:immunology; D014611:Vaccination; D014614:Vaccines, Synthetic
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D014614:Vaccines, Synthetic; D007371:Interferon-gamma; D019746:Intramolecular Oxidoreductases; C042501:dopachrome isomerase