title: PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients.
abstract: The programmed death 1 (PD-1) receptor is a negative regulator of activated T cells and is up-regulated on exhausted virus-specific CD8(+) T cells in chronically infected mice and humans. Programmed death ligand 1 (PD-L1) is expressed by multiple tumors, and its interaction with PD-1 resulted in tumor escape in experimental models. To investigate the role of PD-1 in impairing spontaneous tumor Ag-specific CD8(+) T cells in melanoma patients, we have examined the effect of PD-1 expression on ex vivo detectable CD8(+) T cells specific to the tumor Ag NY-ESO-1. In contrast to EBV, influenza, or Melan-A/MART-1-specific CD8(+) T cells, NY-ESO-1-specific CD8(+) T cells up-regulated PD-1 expression. PD-1 up-regulation on spontaneous NY-ESO-1-specific CD8(+) T cells occurs along with T cell activation and is not directly associated with an inability to produce cytokines. Importantly, blockade of the PD-1/PD-L1 pathway in combination with prolonged Ag stimulation with PD-L1(+) APCs or melanoma cells augmented the number of cytokine-producing, proliferating, and total NY-ESO-1-specific CD8(+) T cells. Collectively, our findings support the role of PD-1 as a regulator of NY-ESO-1-specific CD8(+) T cell expansion in the context of chronic Ag stimulation. They further support the use of PD-1/PD-L1 pathway blockade in cancer patients to partially restore NY-ESO-1-specific CD8(+) T cell numbers and functions, increasing the likelihood of tumor regression.
authors.affiliation: Department of Medicine and Division of Hematology/Oncology, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Fourcade
authors.forename: Pavol
authors.initials: P
authors.lastname: Kudela
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Sun
authors.forename: Hongmei
authors.initials: H
authors.lastname: Shen
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Land
authors.forename: Diana
authors.initials: D
authors.lastname: Lenzner
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Immanuel F
authors.initials: IF
authors.lastname: Luescher
authors.forename: Cindy
authors.initials: C
authors.lastname: Sander
authors.forename: Soldano
authors.initials: S
authors.lastname: Ferrone
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Hassane M
authors.initials: HM
authors.lastname: Zarour
mesh_terms: D015703:Antigens, CD / Q000096:biosynthesis / Q000502:physiology*; D000951:Antigens, Neoplasm / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D015703:Antigens, CD; D000951:Antigens, Neoplasm; D051017:Apoptosis Regulatory Proteins; C104948:CTAG1B protein, human; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor