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

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 (IL)-2, a critical cytokine in 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 anti-tumor 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-2Ra 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. Finally, we find 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE213440 | GEO | 2022/12/02

REPOSITORIES: GEO

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

Project description: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 (IL)-2, a critical cytokine in 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 anti-tumor 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-2Ra 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. Finally, we find 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.

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Project description:The purpose of this study was to examine how Mtb integrates acidic pH and available carbon sources as environmental cues to regulate its metabolism and growth rate. RNA-seq transcriptional profiling of M. tuberculosis growing at acidic or neutral pH, in pyruvate or glycerol, was examined. These studies identified carbon source-dependent and -independent pH-dependent adaptations.

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HUVECs with endogenous or overexpressed GPR4 treated with pH 8.4 (control) or pH 6.4 for 5 h

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