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Updated: Aug 19, 2025
Establishment of an Extracellular Acidic pH Culture System
Published on: November 19, 2017
IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein
Silvia Gaggero1, Jonathan Martinez-Fabregas2, Adeline Cozzani1
1Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital, Lille, France.
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.
Insights
Tumor acidity impairs interleukin-2 (IL-2) immune signaling. A novel IL-2 variant, Switch-2, overcomes this pH limitation, enhancing T cell immunity and tumor rejection with reduced toxicity.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- Cytokine-receptor interactions govern immune responses.
- Extracellular space physicochemical properties' impact on cytokine signaling is not fully understood.
- Interleukin-2 (IL-2) is crucial for T cell immunity.
Purpose of the Study:
- To investigate the influence of tumor microenvironment pH on IL-2 signaling.
- To develop a pH-resilient IL-2 variant for improved cancer immunotherapy.
Main Methods:
- Analysis of IL-2 activity in acidic tumor conditions.
- Directed evolution to engineer a pH-selective IL-2 mutein (Switch-2).
- Assessment of Switch-2's binding affinity, STAT5 activation, and T cell effector function in vitro and in vivo.
Main Results:
- Tumor-generated lactic acid creates an acidic environment that inhibits IL-2 signaling, STAT5 activation, and CD8+ T cell antitumor immunity.
- Switch-2 exhibits enhanced binding to IL-2Rα and potent T cell activation at acidic pH.
- High-dose Switch-2 therapy promotes significant immune activation and tumor rejection with decreased toxicity.
Conclusions:
- pH is a critical factor modulating IL-2 activity and efficacy in tumors.
- Switch-2 represents a promising therapeutic strategy for enhancing cancer immunotherapy by overcoming acidic tumor microenvironments.
- pH sensitivity is a generalizable feature of cytokines, impacting diverse immune processes and therapeutic applications.
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