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

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

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

Harvard

Gaggero, S, Martinez-Fabregas, J, Cozzani, A, Fyfe, PK, Leprohon, M, Yang, J, Thomasen, FE, Winkelmann, H, Magnez, R, Conti, AG, Wilmes, S, Pohler, E, van Gijsel Bonnello, M, Thuru, X, Quesnel, B, Soncin, F, Piehler, J, Lindorff-Larsen, K, Roychoudhuri, R, Moraga, I & Mitra, S 2022, 'IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein', Science immunology, vol. 7, no. 78, eade5686. https://doi.org/10.1126/sciimmunol.ade5686

APA

Gaggero, S., Martinez-Fabregas, J., Cozzani, A., Fyfe, P. K., Leprohon, M., Yang, J., Thomasen, F. E., Winkelmann, H., Magnez, R., Conti, A. G., Wilmes, S., Pohler, E., van Gijsel Bonnello, M., Thuru, X., Quesnel, B., Soncin, F., Piehler, J., Lindorff-Larsen, K., Roychoudhuri, R., ... Mitra, S. (2022). IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein. Science immunology, 7(78), [eade5686]. https://doi.org/10.1126/sciimmunol.ade5686

Vancouver

Gaggero S, Martinez-Fabregas J, Cozzani A, Fyfe PK, Leprohon M, Yang J et al. IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein. Science immunology. 2022;7(78). eade5686. https://doi.org/10.1126/sciimmunol.ade5686

Author

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. / IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein. In: Science immunology. 2022 ; Vol. 7, No. 78.

Bibtex

@article{3c33c9f3fdd84d98a3d8b1caf9b636dc,
title = "IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein",
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.",
author = "Silvia Gaggero and Jonathan Martinez-Fabregas and Adeline Cozzani and Fyfe, {Paul K.} and Malo Leprohon and Jie Yang and Thomasen, {F. Emil} and Hauke Winkelmann and Romain Magnez and Conti, {Alberto G.} and Stephan Wilmes and Elizabeth Pohler and {van Gijsel Bonnello}, Manuel and Xavier Thuru and Bruno Quesnel and Fabrice Soncin and Jacob Piehler and Kresten Lindorff-Larsen and Rahul Roychoudhuri and Ignacio Moraga and Suman Mitra",
year = "2022",
doi = "10.1126/sciimmunol.ade5686",
language = "English",
volume = "7",
journal = "Advances in Immunology",
issn = "0065-2776",
publisher = "American Association for the Advancement of Science",
number = "78",

}

RIS

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

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