IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein
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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.
In: Science immunology, Vol. 7, No. 78, eade5686, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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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
PY - 2022
Y1 - 2022
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.
U2 - 10.1126/sciimmunol.ade5686
DO - 10.1126/sciimmunol.ade5686
M3 - Journal article
C2 - 36459543
AN - SCOPUS:85143336313
VL - 7
JO - Advances in Immunology
JF - Advances in Immunology
SN - 0065-2776
IS - 78
M1 - eade5686
ER -
ID: 329196061