IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein

DOI: 10.1126/sciimmunol.ade5686

Authors: Silvia Gaggero (Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital) , Jonathan Martinez-Fabregas (University of Dundee) , Adeline Cozzani (Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital) , Paul K. Fyfe (University of Dundee) , Malo Leprohon (Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital; Université de Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille) , Jie Yang (University of Cambridge) , F. Emil Thomasen (University of Copenhagen) , Hauke Winkelmann (Osnabrück University) , Romain Magnez (Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital) , Alberto G. Conti (University of Cambridge) , Stephan Wilmes (University of Dundee) , Elizabeth Pohler (University of Dundee) , Manuel Van Gijsel Bonnello (University of Dundee) , Xavier Thuru (Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital) , Bruno Quesnel (Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital) , Fabrice Soncin (CNRS/IIS/Centre Oscar Lambret/Lille University SMMiL-E Project, CNRS Délégation Hauts-de-France; University of Tokyo) , Jacob Piehler (Osnabrück University) , Kresten Lindorff-Larsen (University of Copenhagen) , Rahul Roychoudhuri (University of Cambridge) , Ignacio Moraga (University of Dundee) , Suman Mitra (Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Science Immunology , VOL 7

State: Published (Approved)
Published: December 2022

Abstract: 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.

Diamond Keywords: Immunotherapy

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

Added On: 07/12/2022 09:10

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)