title: Proportions of blood-borne Vδ1+ and Vδ2+ T-cells are associated with overall survival of melanoma patients treated with ipilimumab.
abstract: Human γδ T-cells possess regulatory and cytotoxic capabilities, and could potentially influence the efficacy of immunotherapies. We analysed the frequencies of peripheral γδ T-cells, including their most prominent subsets (Vδ1+ and Vδ2+ cells) and differentiation states in 109 melanoma patients and 109 healthy controls. We additionally analysed the impact of γδ T-cells on overall survival (OS) calculated from the first dose of ipilimumab in melanoma patients. Higher median frequencies of Vδ1+ cells and lower median frequencies of Vδ2+ cells were identified in patients compared to healthy subjects (Vδ1+: 30% versus 15%, Vδ2+: 39% versus 64%, both p < 0.001). Patients with higher frequencies of Vδ1+ cells (≥30%) had poorer OS (p = 0.043) and a Vδ1+ differentiation signature dominated by late-differentiated phenotypes. In contrast, higher frequencies of Vδ2+ cells (≥39%) were associated with longer survival (p = 0.031) independent of the M category or lactate dehydrogenase level. Patients with decreasing frequencies of Vδ2+ cells under ipilimumab treatment had worse OS and a lower rate of clinical benefit than patients without such decreases. Therefore, we suggest frequencies of both Vδ1+ and Vδ2+ cells as candidate biomarkers for outcome in melanoma patients following ipilimumab. Further studies are needed to validate these results and to clarify whether they represent prognostic associations or whether γδ T-cells are specifically and/or functionally linked to the mode of action of ipilimumab.
authors.affiliation: Department of Dermatology, University Medical Center, Tübingen, Germany; Department of Internal Medicine II, University Medical Center, Tübingen, Germany. Electronic address: Kilian.Wistuba-Hamprecht@uni-tuebingen.de.
authors.forename: Kilian
authors.initials: K
authors.lastname: Wistuba-Hamprecht
authors.affiliation: Department of Dermatology, University Medical Center, Tübingen, Germany; Department of Internal Medicine II, University Medical Center, Tübingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Martens
authors.affiliation: Department of Internal Medicine II, University Medical Center, Tübingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Haehnel
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Marnix
authors.initials: M
authors.lastname: Geukes Foppen
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Postow
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Phillip
authors.initials: P
authors.lastname: Wong
authors.affiliation: Department of Oncology, Immunotherapy Unit, INSERM U932, Institut Curie, Paris, France.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Romano
authors.affiliation: Department of Oncodermatology, INSERM Research Unit 892, University Hospital, Nantes, France.
authors.forename: Amir
authors.initials: A
authors.lastname: Khammari
authors.affiliation: Department of Oncodermatology, INSERM Research Unit 892, University Hospital, Nantes, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dreno
authors.affiliation: Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy.
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Capone
authors.affiliation: Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Research Group on Geriatrics, Charité - Universitaetsmedizin, Berlin, Germany; Institute of Medical and Human Genetics, Charité - Universitätsmedizin Berlin, Germany.
authors.forename: Ilja
authors.initials: I
authors.lastname: Demuth
authors.affiliation: Research Group on Geriatrics, Charité - Universitaetsmedizin, Berlin, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Steinhagen-Thiessen
authors.affiliation: Singapore Immunology Network, Agency for Science, Technology and Research, Singapore.
authors.forename: Anis
authors.initials: A
authors.lastname: Larbi
authors.affiliation: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Schilling
authors.affiliation: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Christian U
authors.initials: CU
authors.lastname: Blank
authors.affiliation: Department of Internal Medicine II, University Medical Center, Tübingen, Germany; School of Science and Technology, College of Arts and Science, Nottingham Trent University, Nottingham, UK; Division of Cancer Studies, Faculty of Life Sciences and Medicine, King's College London, London, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Pawelec
authors.affiliation: Department of Dermatology, University Medical Center, Tübingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.affiliation: Department of Dermatology, University Medical Center, Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood*; D016022:Case-Control Studies; D002454:Cell Differentiation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology*; D008875:Middle Aged; D011379:Prognosis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000097:blood*; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000074324:Ipilimumab; D016692:Receptors, Antigen, T-Cell, gamma-delta
keywords: Biomarker; Immunotherapy; Ipilimumab; Melanoma; Survival; γδ T-cells