Engineering cytokine-receptor pairs Interleukin-2 (IL-2) is an important cytokine that helps T cells destroy tumors and virus-infected cells. IL-2 has great therapeutic promise but is limited by toxic side effects and its capacity to both activate and repress immune responses. Sockolosky et al. set out to improve IL-2–based immunotherapy by engineering synthetic IL-2–receptor pairs (i.e., IL-2 and its receptor, IL-2R) (see the Perspective by Mackall). Engineered complexes transmitted IL-2 signals but only interacted with each other and not with endogenous IL-2/IL-2R. Treatment of mice with IL-2 improved the ability of engineered T cells to reject tumors with no obvious side effects. This type of approach may provide a way to mitigate toxicities associated with some cytokine-based immunotherapies. Science, this issue p. 1037; see also p. 990 Engineered cytokines are able to improve immunotherapy in mouse tumor models. Interleukin-2 (IL-2) is a cytokine required for effector T cell expansion, survival, and function, especially for engineered T cells in adoptive cell immunotherapy, but its pleiotropy leads to simultaneous stimulation and suppression of immune responses as well as systemic toxicity, limiting its therapeutic use. We engineered IL-2 cytokine-receptor orthogonal (ortho) pairs that interact with one another, transmitting native IL-2 signals, but do not interact with their natural cytokine and receptor counterparts. Introduction of orthoIL-2Rβ into T cells enabled the selective cellular targeting of orthoIL-2 to engineered CD4+ and CD8+ T cells in vitro and in vivo, with limited off-target effects and negligible toxicity. OrthoIL-2 pairs were efficacious in a preclinical mouse cancer model of adoptive cell therapy and may therefore represent a synthetic approach to achieving selective potentiation of engineered cells.

中文翻译：

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使用正交 IL-2 细胞因子受体复合物选择性靶向工程化 T 细胞

工程细胞因子-受体对白细胞介素 2 (IL-2) 是一种重要的细胞因子，可帮助 T 细胞破坏肿瘤和病毒感染的细胞。IL-2 具有很大的治疗前景，但受到毒副作用及其激活和抑制免疫反应的能力的限制。Sockolosky 等人。着手通过设计合成的 IL-2 受体对（即 IL-2 及其受体 IL-2R）来改进基于 IL-2 的免疫疗法（参见 Mackall 的 Perspective）。工程复合物传递 IL-2 信号，但仅相互相互作用，而不与内源性 IL-2/IL-2R 相互作用。用 IL-2 治疗小鼠提高了工程化 T 细胞排斥肿瘤的能力，并且没有明显的副作用。这种类型的方法可以提供一种减轻与某些基于细胞因子的免疫疗法相关的毒性的方法。科学，本期第 3 页。1037; 另见第 990 工程细胞因子能够改善小鼠肿瘤模型的免疫治疗。白细胞介素 2 (IL-2) 是效应 T 细胞扩增、存活和功能所需的细胞因子，尤其是过继细胞免疫疗法中的工程化 T 细胞，但其多效性导致同时刺激和抑制免疫反应以及全身毒性，限制其治疗用途。我们设计了 IL-2 细胞因子-受体正交（邻位）对，它们彼此相互作用，传递天然 IL-2 信号，但不与其天然细胞因子和受体对应物相互作用。将 orthoIL-2Rβ 引入 T 细胞使 orthoIL-2 在体外和体内选择性细胞靶向工程化 CD4+ 和 CD8+ T 细胞，脱靶效应有限且毒性可忽略不计。