Inserm UMR1277, CNRS UMR9020-CANTHER, Université de Lille, Lille University Hospital, Lille, France.
Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
Sci Immunol. 2022 Dec 9;7(78):eade5686. doi: 10.1126/sciimmunol.ade5686. Epub 2022 Dec 2.
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.
细胞因子在细胞外空间与受体相互作用，以控制免疫反应。细胞外空间的物理化学特性如何影响细胞因子信号传递，目前还不完全清楚。在这里，我们表明白细胞介素 2（IL-2）的活性，一种对 T 细胞免疫至关重要的细胞因子，受到 pH 值的深刻影响，在肿瘤的酸性环境中限制了 IL-2 的信号传递。肿瘤产生的乳酸限制了 CD8 T 细胞中 STAT5 的激活、效应器分化和抗肿瘤免疫，并使高剂量 IL-2 治疗效果不佳。定向进化使选择 pH 选择性 IL-2 突变体（Switch-2）成为可能。Switch-2 与白细胞介素 2 受体亚单位 IL-2Rα 的结合亲和力更高，在酸性 pH 值下比中性 pH 值更能触发 STAT5 的激活，并更有效地驱动 CD8 T 细胞效应功能。因此，高剂量 Switch-2 治疗在正常组织中降低了靶毒性，同时引发了强烈的免疫激活和肿瘤排斥。最后，我们表明，对 pH 值的敏感性是一种具有广泛免疫和免疫治疗相关性的广泛细胞因子的普遍特性。
