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Nat Commun. 2017 Sep 19;8(1):592. doi: 10.1038/s41467-017-00608-2.

Predictors of responses to immune checkpoint blockade in advanced melanoma.

Author information

1
INSERM U1015, Gustave Roussy Cancer Campus, Villejuif, 94800, France.
2
University Paris-Saclay, Kremlin Bicêtre, 94 276, France.
3
Gustave Roussy Cancer Campus, Villejuif, 94800, France.
4
Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Campus, Villejuif, 94800, France.
5
CIC1428, Gustave Roussy Cancer Campus, Villejuif, 94800, France.
6
Gustave Roussy, Université Paris-Saclay, Service de Biostatistique et d'Epidémiologie, Villejuif, F-94805, France.
7
Saint Antoine Hospital, INSERM ERL 1157-CNRS UMR 7203, Paris, 75005, France.
8
Laura & Isaac Perlmutter Cancer Center, New York University Medical Center, New York, NY, 10016, USA.
9
Center for Cancer Immune Therapy, Department of Hematology and Oncology, Copenhagen University Hospital, Herlev, DK-2730, Denmark.
10
The Lautenberg Center for General and Tumor Immunology, BioMedical Research institute Israel Canada of the Faculty of Medicine, The Hebrew University Hadassah Medical School, Jerusalem, 91120, Israel.
11
Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, CA, 94143, USA.
12
Department of Immunobiology, Yale School of Medicine, 10 Amistad Street, New Haven, CT, 06519, USA.
13
Eutilex, Suite# 1401 Daeryung Technotown 17 Gasan Digital 1-ro 25, Geumcheon-gu, Seoul, 08594, Korea.
14
Section of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA, 70112, USA.
15
Evergrande Center for Immunologic Diseases and Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
16
Department of Dermatology, University Medical Center Tübingen, Tübingen, 72076, Germany.
17
Université de Franche Comté, EA3181, SFR4234, Service de Dermatologie, Centre Hospitalier Universitaire (CHU), Besançon, 25000, France.
18
Department of Medical Oncology, University Hospital of Besancon, 3 Boulevard Alexander Fleming, Besancon, F-25030, France.
19
Clinical Investigational Centre, CIC-1431, University Hospital of Besançon, Besançon, 25030, France.
20
INSERM U1098, University of Franche-Comté, Besançon, 25020, France.
21
Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon and University Claude Bernard Lyon 1, Lyon, 69000, France.
22
Centre de Recherche en Cancérologie de Lyon, Lyon, 69000, France.
23
Department of Pathology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, 69000, France.
24
Department of Pathology, Gustave Roussy Cancer Campus, Villejuif, 94800, France.
25
Medical Oncology and Immunotherapy Division, University Hospital of Siena, Viale Bracci, 14, Siena, 53100, Italy.
26
Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Instituto Toscano Tumori, Siena, 53100, Italy.
27
Department of Dermatology, University Hospital, University Duisburg-Essen, Essen, Germany & German Cancer Consortium (DKTZ), Heidelberg, D-69120, Germany.
28
Division of Gene Therapy and Hepatology, Centre for Applied Medical Research, Pamplona, 31008, Spain.
29
Oncology Department, University Clinic of Navarra, Pamplona, 31008, Spain.
30
Centro de Investigación cBiomedica en Red de Oncologia, Pamplona, 31008, Spain.
31
Department of Onco-dermatology, CIC Biotherapy, INSERM U1232, CHU Nantes, Nantes, 44000, France.
32
Department of Dermatology, University Hospital Zürich and University of Zürich, Zürich, 8091, Switzerland.
33
Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 97213, USA.
34
Sharett Institute of Oncology, Hadassah Medical Organization, Jerusalem, 91120, Israel.
35
Department of Oncology, Aarhus University Hospital, Aarhus, DK-8200, Denmark.
36
INSERM U1138, Centre de Recherche des Cordeliers, Paris, 75006, France.
37
Equipe 11 labellisée par la Ligue contre le Cancer, Centre de Recherche des Cordeliers, Paris, 75006, France.
38
Université Paris Descartes, Sorbonne Paris Cité, Paris, 75006, France.
39
Université Pierre et Marie Curie, Paris, 75005, France.
40
Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, 75015, France.
41
Department of Surgery, Gustave Roussy Cancer Center, Villejuif, 94800, France.
42
Department of Dermatology, Gustave Roussy Cancer Center, Villejuif, 94800, France.
43
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD, 4006, Australia.
44
School of Medicine, University of Queensland, Herston, QLD, 4006, Australia.
45
INSERM U1015, Gustave Roussy Cancer Campus, Villejuif, 94800, France. Laurence.ZITVOGEL@gustaveroussy.fr.
46
University Paris-Saclay, Kremlin Bicêtre, 94 276, France. Laurence.ZITVOGEL@gustaveroussy.fr.
47
Gustave Roussy Cancer Campus, Villejuif, 94800, France. Laurence.ZITVOGEL@gustaveroussy.fr.
48
CIC1428, Gustave Roussy Cancer Campus, Villejuif, 94800, France. Laurence.ZITVOGEL@gustaveroussy.fr.
49
Gustave Roussy, Université Paris-Saclay, Service de Biostatistique et d'Epidémiologie, Villejuif, F-94805, France. Laurence.ZITVOGEL@gustaveroussy.fr.

Abstract

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB. Based on this assay, we retrospectively observed, in eight cohorts enrolling 190 MMel patients treated with ipilimumab, that PD-L1 expression on peripheral T cells was prognostic on overall and progression-free survival. Moreover, detectable CD137 on circulating CD8+ T cells was associated with the disease-free status of resected stage III MMel patients after adjuvant ipilimumab + nivolumab (but not nivolumab alone). These biomarkers should be validated in prospective trials in MMel.The clinical management of metastatic melanoma requires predictors of the response to checkpoint blockade. Here, the authors use immunological assays to identify potential prognostic/predictive biomarkers in circulating blood cells and in tumor-infiltrating lymphocytes from patients with resected stage III melanoma.

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