title: PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8⁺ T cells induced by melanoma vaccines.
abstract: Although melanoma vaccines stimulate tumor antigen-specific CD8(+) T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we evaluated the character of vaccine-induced CD8(+) T cells with regard to the inhibitory T-cell coreceptors PD-1 and Tim-3 in patients with metastatic melanoma who were administered tumor vaccines. The vaccines included incomplete Freund's adjuvant, CpG oligodeoxynucleotide (CpG), and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V, either by itself or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid tumor antigen-specific CD8(+) T-cell responses detected ex vivo, however, tumor antigen-specific CD8(+) T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8(+) T cells upregulated PD-1 and a minority also upregulated Tim-3. Levels of PD-1 and Tim-3 expression by vaccine-induced CD8(+) T cells at the time of vaccine administration correlated inversely with their expansion in vivo. Dual blockade of PD-1 and Tim-3 enhanced the expansion and cytokine production of vaccine-induced CD8(+) T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades with cancer vaccines to stimulate potent antitumor T-cell responses and increase the likelihood of clinical responses in patients with advanced melanoma.
authors.affiliation: Authors' Affiliations: Division of Hematology/Oncology, Department of Medicine; Departments of Immunology and Biostatistics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Pfizer, Cambridge; and Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; and Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland.
authors.forename: Julien
authors.initials: J
authors.lastname: Fourcade
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Sun
authors.forename: Ornella
authors.initials: O
authors.lastname: Pagliano
authors.forename: Joe-Marc
authors.initials: JM
authors.lastname: Chauvin
authors.forename: Cindy
authors.initials: C
authors.lastname: Sander
authors.forename: Bratislav
authors.initials: B
authors.lastname: Janjic
authors.forename: Ahmad A
authors.initials: AA
authors.lastname: Tarhini
authors.forename: Hussein A
authors.initials: HA
authors.lastname: Tawbi
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Stergios
authors.initials: S
authors.lastname: Moschos
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Immanuel F
authors.initials: IF
authors.lastname: Luescher
authors.forename: Arthur
authors.initials: A
authors.lastname: Krieg
authors.forename: Ana C
authors.initials: AC
authors.lastname: Anderson
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
authors.forename: Hassane M
authors.initials: HM
authors.lastname: Zarour
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology / Q000502:physiology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D049109:Cell Proliferation; D005620:Freund's Adjuvant / Q000627:therapeutic use; D000072597:Hepatitis A Virus Cellular Receptor 2; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008055:Lipids / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000235:genetics*; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D008565:Membrane Proteins / Q000502:physiology*; D009838:Oligodeoxyribonucleotides / Q000627:therapeutic use; D061026:Programmed Cell Death 1 Receptor / Q000502:physiology*; D037182:T-Cell Antigen Receptor Specificity; D016896:Treatment Outcome
chemical_list: C408982:CPG-oligonucleotide; D019496:Cancer Vaccines; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D008055:Lipids; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C114843:incomplete Freund's adjuvant; D007371:Interferon-gamma; D005620:Freund's Adjuvant