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Cell Res. 2015 Feb;25(2):208-24. doi: 10.1038/cr.2015.3. Epub 2015 Jan 13.

Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25.

Author information

1
1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U1015, Villejuif, France [3] Université Paris Sud-XI, Faculté de Médecine, Le Kremlin Bicêtre, France.
2
1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U848, Villejuif, France [3] Metabolomics Platform, Institut Gustave Roussy, Villejuif, France.
3
1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U1015, Villejuif, France [3] Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 507, Villejuif, France.
4
1] INSERM, Unité Mixte de Recherche_S959, I, Paris, France [2] Assistance-Publique Hopitaux de Paris, Hôpital Pitié-Salpêtrière, Biotherapy, Paris, France.
5
INSERM U753, Villejuif, France.
6
1] Gustave Roussy Cancer Campus, Villejuif, France [2] Department of Medical Oncology, IGR, Villejuif, France.
7
Department of Immunology, MD Anderson Cancer Center, Houston, TX, USA.
8
University of California Los Angeles, Los Angeles, CA, USA.
9
Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
10
1] Department of Diagnostics and Cancer Immunology, Greater Poland Cancer Centre, Poznan, Poland [2] Chair of Medical Biotechnology, Poznan University of Medical Sciences, Poznan, Poland.
11
Department of Dermatology, University Hospital Essen, Germany.
12
National Center for Tumor Diseases, University Hospital, Heidelberg, Germany.
13
Bristol-Myers Squibb, Redwood City, CA, USA.
14
Earle A Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA.
15
Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
16
1] QIMR Berghofer Medical Research Institute, Herston, 4006, Queensland, Australia [2] School of Medicine, The University of Queensland, Herston, QLD 4006, Queensland, Australia.
17
1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U1015, Villejuif, France [3] INSERM U981, Villejuif, France.
18
1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U1015, Villejuif, France [3] Department of Medical Oncology, IGR, Villejuif, France [4] INSERM U981, Villejuif, France.
19
1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U848, Villejuif, France [3] Metabolomics Platform, Institut Gustave Roussy, Villejuif, France [4] Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France [5] Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France [6] Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
20
1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U1015, Villejuif, France [3] Université Paris Sud-XI, Faculté de Médecine, Le Kremlin Bicêtre, France [4] Department of Medical Oncology, IGR, Villejuif, France.

Abstract

The cytotoxic T lymphocyte antigen-4 (CTLA-4)-blocking antibody ipilimumab induces immune-mediated long-term control of metastatic melanoma in a fraction of patients. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, thus far clinically useful, immunologically relevant biomarkers that predict treatment efficiency have been elusive. Here, we show that neutralization of IL-2 or blocking the α and β subunits of the IL-2 receptor (CD25 and CD122, respectively) abolished the antitumor effects and the accompanying improvement of the ratio of intratumoral T effector versus regulatory cells (Tregs), which were otherwise induced by CTLA-4 blockade in preclinical mouse models. CTLA-4 blockade led to the reduction of a suppressive CD4(+) T cell subset expressing Lag3, ICOS, IL-10 and Egr2 with a concomitant rise in IL-2-producing effector cells that lost FoxP3 expression and accumulated in regressing tumors. While recombinant IL-2 improved the therapeutic efficacy of CTLA-4 blockade, the decoy IL-2 receptor α (IL-2Rα, sCD25) inhibited the anticancer effects of CTLA-4 blockade. In 262 metastatic melanoma patients receiving ipilimumab, baseline serum concentrations of sCD25 represented an independent indicator of overall survival, with high levels predicting resistance to therapy. Altogether, these results unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides the first immunologically relevant biomarker, namely elevated serum sCD25, that predicts resistance to CTLA-4 blockade in patients with melanoma.

PMID:
25582080
PMCID:
PMC4650573
DOI:
10.1038/cr.2015.3
[Indexed for MEDLINE]
Free PMC Article
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