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IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein.
Gaggero, Silvia; Martinez-Fabregas, Jonathan; Cozzani, Adeline; Fyfe, Paul K; Leprohon, Malo; Yang, Jie; Thomasen, F Emil; Winkelmann, Hauke; Magnez, Romain; Conti, Alberto G; Wilmes, Stephan; Pohler, Elizabeth; van Gijsel Bonnello, Manuel; Thuru, Xavier; Quesnel, Bruno; Soncin, Fabrice; Piehler, Jacob; Lindorff-Larsen, Kresten; Roychoudhuri, Rahul; Moraga, Ignacio; Mitra, Suman.
Afiliação
  • Gaggero S; Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital, Lille, France.
  • Martinez-Fabregas J; Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
  • Cozzani A; Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital, Lille, France.
  • Fyfe PK; Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
  • Leprohon M; Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital, Lille, France.
  • Yang J; Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, US 41 - UAR 2014 - PLBS, F-59000 Lille, France.
  • Thomasen FE; Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK.
  • Winkelmann H; Structural Biology and NMR Laboratory, Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark.
  • Magnez R; Department of Biology/Chemistry and Center for Cellular Nanoanalytics (CellNanOs), Osnabrück University, Barbarastr. 11, 49076 Osnabrück, Germany.
  • Conti AG; Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital, Lille, France.
  • Wilmes S; Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK.
  • Pohler E; Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
  • van Gijsel Bonnello M; Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
  • Thuru X; Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
  • Quesnel B; Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital, Lille, France.
  • Soncin F; Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital, Lille, France.
  • Piehler J; CNRS/IIS/Centre Oscar Lambret/Lille University SMMiL-E Project, CNRS Délégation Hauts-de-France, Lille, France.
  • Lindorff-Larsen K; CNRS IRL 2820; Laboratory for Integrated Micro Mechatronic Systems, Institute of Industrial Science, University of Tokyo, Tokyo, Japan.
  • Roychoudhuri R; Department of Biology/Chemistry and Center for Cellular Nanoanalytics (CellNanOs), Osnabrück University, Barbarastr. 11, 49076 Osnabrück, Germany.
  • Moraga I; Structural Biology and NMR Laboratory, Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark.
  • Mitra S; Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, UK.
Sci Immunol ; 7(78): eade5686, 2022 12 09.
Article em En | MEDLINE | ID: mdl-36459543
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Interleucina-2 / Neoplasias Limite: Humans Idioma: En Revista: Sci Immunol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: França

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Interleucina-2 / Neoplasias Limite: Humans Idioma: En Revista: Sci Immunol Ano de publicação: 2022 Tipo de documento: Article País de afiliação: França