title: Anticancer immunotherapy by CTLA-4 blockade: obligatory contribution of IL-2 receptors and negative prognostic impact of soluble CD25.
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.
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U1015, Villejuif, France [3] Université Paris Sud-XI, Faculté de Médecine, Le Kremlin Bicêtre, France.
authors.forename: Dalil
authors.initials: D
authors.lastname: Hannani
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U1015, Villejuif, France [3] Université Paris Sud-XI, Faculté de Médecine, Le Kremlin Bicêtre, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Vétizou
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U848, Villejuif, France [3] Metabolomics Platform, Institut Gustave Roussy, Villejuif, France.
authors.forename: David
authors.initials: D
authors.lastname: Enot
authors.affiliation: 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.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Rusakiewicz
authors.affiliation: 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.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chaput
authors.affiliation: 1] INSERM, Unité Mixte de Recherche_S959, I, Paris, France [2] Assistance-Publique Hopitaux de Paris, Hôpital Pitié-Salpêtrière, Biotherapy, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.affiliation: 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.
authors.forename: Melanie
authors.initials: M
authors.lastname: Desbois
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U1015, Villejuif, France [3] Université Paris Sud-XI, Faculté de Médecine, Le Kremlin Bicêtre, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jacquelot
authors.affiliation: 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.
authors.forename: Nadège
authors.initials: N
authors.lastname: Vimond
authors.affiliation: INSERM U753, Villejuif, France.
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France [2] Department of Medical Oncology, IGR, Villejuif, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Mateus
authors.affiliation: Department of Immunology, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.affiliation: University of California Los Angeles, Los Angeles, CA, USA.
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Philip
authors.initials: P
authors.lastname: Wong
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Department of Immunology, and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Postow
authors.affiliation: 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.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Mackiewicz
authors.affiliation: 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.
authors.forename: Jacek
authors.initials: J
authors.lastname: Mackiewicz
authors.affiliation: Department of Dermatology, University Hospital Essen, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorff
authors.affiliation: National Center for Tumor Diseases, University Hospital, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jaeger
authors.forename: Inka
authors.initials: I
authors.lastname: Zörnig
authors.forename: Jessica
authors.initials: J
authors.lastname: Hassel
authors.affiliation: Bristol-Myers Squibb, Redwood City, CA, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Korman
authors.affiliation: Earle A Chiles Research Institute, Robert W. Franz Cancer Center, Providence Portland Medical Center, Portland, OR, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Bahjat
authors.affiliation: Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
authors.affiliation: Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Calabro
authors.affiliation: 1] QIMR Berghofer Medical Research Institute, Herston, 4006, Queensland, Australia [2] School of Medicine, The University of Queensland, Herston, QLD 4006, Queensland, Australia.
authors.forename: Michele Wl
authors.initials: MW
authors.lastname: Teng
authors.affiliation: 1] QIMR Berghofer Medical Research Institute, Herston, 4006, Queensland, Australia [2] School of Medicine, The University of Queensland, Herston, QLD 4006, Queensland, Australia.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.affiliation: 1] Gustave Roussy Cancer Campus, Villejuif, France [2] INSERM U1015, Villejuif, France [3] INSERM U981, Villejuif, France.
authors.forename: Alexander
authors.initials: A
authors.lastname: Eggermont
authors.affiliation: 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.
authors.forename: Caroline
authors.initials: C
authors.lastname: Robert
authors.affiliation: 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.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: 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.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000276:immunology / Q000378:metabolism*; D015331:Cohort Studies; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007167:Immunotherapy; D053645:Interleukin-2 Receptor alpha Subunit / Q000097:blood* / Q000276:immunology; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D060908:CTLA-4 Antigen; D053645:Interleukin-2 Receptor alpha Subunit; D000074324:Ipilimumab; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins