TY - JOUR
T1 - IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein
AU - Gaggero, Silvia
AU - Martinez-Fabregas, Jonathan
AU - Cozzani, Adeline
AU - Fyfe, Paul K.
AU - Leprohon, Malo
AU - Yang, Jie
AU - Thomasen, F. Emil
AU - Winkelmann, Hauke
AU - Magnez, Romain
AU - Conti, Alberto G.
AU - Wilmes, Stephan
AU - Pohler, Elizabeth
AU - van Gijsel Bonnello, Manuel
AU - Thuru, Xavier
AU - Quesnel, Bruno
AU - Soncin, Fabrice
AU - Piehler, Jacob
AU - Lindorff-Larsen, Kresten
AU - Roychoudhuri, Rahul
AU - Moraga, Ignacio
AU - Mitra, Suman
N1 - Funding Information:
This work was supported by DFG grant SFB 944-P8 (J.P.), Ligue Nationale Contre Le Cancer grant R20024EE (S.M.), Fondation Arc Pour La Recherche Sur Le Cancer grant R20026EE (S.M.), Contrat de Plan Etat-Région CPER Cancer 2015-2020 (CPER) grant SAS18057 (S.M., S.G., and A.C.), Wellcome Trust 202323/Z/16/Z (I.M., J.M.-F., and S.W.), ERC-206-STG (I.M., J.M.-F., and S.W.), UK MRC grant MR/W018454/1 (R.R. and J.Y.), and Wellcome Trust/Royal Society grant 105663/A/14/Z (R.R. and J.Y.).
Copyright:
© 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
PY - 2022/12/2
Y1 - 2022/12/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85143336313&partnerID=8YFLogxK
U2 - 10.1126/sciimmunol.ade5686
DO - 10.1126/sciimmunol.ade5686
M3 - Article
C2 - 36459543
SN - 2470-9468
VL - 7
JO - Science Immunology
JF - Science Immunology
IS - 78
M1 - eade568
ER -