After showing that tumor-derived lactic acid limited IL-2 signaling, STAT5 phosphorylation, and antitumor activity in the TME, Gaggero, Martinez-Fabregas et al. used directed evolution to identify a pH-selective IL-2 mutein (Switch-2) that bound IL-2Rα with higher affinity and drove CD8+ T cell effector function more potently at acidic pH than at neutral pH. Compared to IL-2, Switch-2 therapy elicited potent antitumor immune responses and tumor rejection in a variety of solid tumor models, with decreased systemic on-target activity and toxicity in normal tissues, suggesting this approach could have translational potential for improved cytokine cancer therapy.
Contributed by Katherine Turner
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-2R_ 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.