IL-2 is inactivated by the acidic pH ...
Document type :
Article dans une revue scientifique: Article original
Title :
IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein
Author(s) :
Gaggero, Silvia [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Martinez-Fabregas, Jonathan [Auteur]
Cozzani, Adeline [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Fyfe, Paul [Auteur]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Leprohon, Malo [Auteur]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Yang, Jie [Auteur]
University of Cambridge [UK] [CAM]
Thomasen, F. Emil [Auteur]
Winkelmann, Hauke [Auteur]
Universität Osnabrück - Osnabrück University
Magnez, Romain [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Conti, Alberto [Auteur]
University of Cambridge [UK] [CAM]
Wilmes, Stephan [Auteur]
University of Dundee
Pohler, Elizabeth [Auteur]
University of Dundee
van Gijsel Bonnello, Manuel [Auteur]
University of Dundee
Thuru, Xavier [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Quesnel, Bruno [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Soncin, Fabrice [Auteur]
Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] [UNICANCER/Lille]
Laboratory for Integrated Micro Mechatronics Systems [LIMMS]
Piehler, Jacob [Auteur]
Universität Osnabrück - Osnabrück University
Lindorff-Larsen, Kresten [Auteur]
Roychoudhuri, Rahul [Auteur]
University of Cambridge [UK] [CAM]
Moraga, Ignacio [Auteur]
University of Dundee
Mitra, Suman [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Martinez-Fabregas, Jonathan [Auteur]
Cozzani, Adeline [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Fyfe, Paul [Auteur]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Leprohon, Malo [Auteur]
Plateformes Lilloises en Biologie et Santé - UAR 2014 - US 41 [PLBS]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Yang, Jie [Auteur]
University of Cambridge [UK] [CAM]
Thomasen, F. Emil [Auteur]
Winkelmann, Hauke [Auteur]
Universität Osnabrück - Osnabrück University
Magnez, Romain [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Conti, Alberto [Auteur]
University of Cambridge [UK] [CAM]
Wilmes, Stephan [Auteur]
University of Dundee
Pohler, Elizabeth [Auteur]
University of Dundee
van Gijsel Bonnello, Manuel [Auteur]
University of Dundee
Thuru, Xavier [Auteur]

Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Quesnel, Bruno [Auteur]

Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Soncin, Fabrice [Auteur]

Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] [UNICANCER/Lille]
Laboratory for Integrated Micro Mechatronics Systems [LIMMS]
Piehler, Jacob [Auteur]
Universität Osnabrück - Osnabrück University
Lindorff-Larsen, Kresten [Auteur]
Roychoudhuri, Rahul [Auteur]
University of Cambridge [UK] [CAM]
Moraga, Ignacio [Auteur]
University of Dundee
Mitra, Suman [Auteur]
Hétérogénéité, Plasticité et Résistance aux Thérapies des Cancers = Cancer Heterogeneity, Plasticity and Resistance to Therapies - UMR 9020 - U 1277 [CANTHER]
Journal title :
Science Immunology
Pages :
ade5686
Publisher :
American Association for the Advancement of Science (AAAS)
Publication date :
2022
ISSN :
2470-9468
HAL domain(s) :
Sciences du Vivant [q-bio]/Cancer
Sciences du Vivant [q-bio]/Immunologie/Immunité adaptative
Sciences du Vivant [q-bio]/Immunologie/Immunité innée
Sciences du Vivant [q-bio]/Immunologie/Immunité adaptative
Sciences du Vivant [q-bio]/Immunologie/Immunité innée
English abstract : [en]
Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, ...
Show more >Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin-2 (IL-2), a cytokine critical to T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation, and antitumor immunity by CD8 + T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Rα with higher affinity, triggers STAT5 activation, and drives CD8 + T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Last, we show that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.Show less >
Show more >Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin-2 (IL-2), a cytokine critical to T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation, and antitumor immunity by CD8 + T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Rα with higher affinity, triggers STAT5 activation, and drives CD8 + T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Last, we show that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.Show less >
Language :
Anglais
Peer reviewed article :
Oui
Audience :
Internationale
Popular science :
Non
Collections :
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