title: PD-1 expression on Melan-A-reactive T cells increases during progression to metastatic disease.
abstract: Programmed death 1 (PD-1) is known as an important factor for the development of tolerogenicity. This has been proven in chronic viral infections and different tumor models. To address the role of PD-1 and its ligand programmed death ligand 1 (PD-L1) in different stages of malignant melanoma, we investigated peripheral blood and tumor tissues in regard to overall survival (OS) and prognostic relevance. One hundred samples of peripheral blood mononuclear cells from HLA-A2(+)  patients with malignant melanoma (Stages I-IV) were analyzed in seven color FACS combined with multimer analyses for the immunodominant epitope of Melan-A (peptide A2/Melan-A(p26-35mod) ). Corresponding formalin-fixed paraffin-embedded tissues of primary tumor and distant organ metastases from 37 cases were analyzed by immunohistochemistry for Melan-A, PD-L1 and PD-1 expression. Compared to the total CD8(+)  T cell population, PD-1 expression by A2/Melan-A(+)  CD8(+)  T cells was over-represented in melanoma stages III and IV (p < 0.001). Although elevation of PD-1(+)  Melan-A(+)  CD8(+)  T cells had no significant influence on OS, a positive correlation was observed between PD-L1 expression on melanoma cells and OS (p = 0.05). Correlation of advanced tumor stage with increased A2/Melan-A-multimer(+)  PD-1(+)  T cells in the peripheral blood suggest that blocking of PD-1 could have therapeutic potential in advanced stage melanoma.
authors: Department of Hematology, Universität München, Munich, Germany. h.kroenig@lrz.tum.de
authors: Holger
authors: H
authors: Krönig
authors: Kathrin
authors: K
authors: Julia Falchner
authors: Marcus
authors: M
authors: Odendahl
authors: Bettina
authors: B
authors: Brackertz
authors: Heinke
authors: H
authors: Conrad
authors: Dieter
authors: D
authors: Muck
authors: Rüdiger
authors: R
authors: Hein
authors: Christian
authors: C
authors: Blank
authors: Christian
authors: C
authors: Peschel
authors: Bernhard
authors: B
authors: Haller
authors: Stephan
authors: S
authors: Schulz
authors: Helga
authors: H
authors: Bernhard
mesh_terms: D000368:Aged; D060890:B7-H1 Antigen / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D058965:MART-1 Antigen / Q000378:metabolism*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000556:secondary*; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D012878:Skin Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D058965:MART-1 Antigen; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor