Synthetic receptor signalling has the potential to endow adoptively transferred T cells with new functions that overcome major barriers in the treatment of solid tumours, including the need for conditioning chemotherapy^1,2. Here we designed chimeric receptors that have an orthogonal IL-2 receptor extracellular domain (ECD) fused with the intracellular domain (ICD) of receptors for common γ-chain (γ_c) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γ_c cytokine signal. Of these, T cells that signal through the chimeric orthogonal IL-2Rβ-ECD–IL-9R-ICD (o9R) are distinguished by the concomitant activation of STAT1, STAT3 and STAT5 and assume characteristics of stem cell memory and effector T cells. Compared to o2R T cells, o9R T cells have superior anti-tumour efficacy in two recalcitrant syngeneic mouse solid tumour models of melanoma and pancreatic cancer and are effective even in the absence of conditioning lymphodepletion. Therefore, by repurposing IL-9R signalling using a chimeric orthogonal cytokine receptor, T cells gain new functions, and this results in improved anti-tumour activity for hard-to-treat solid tumours.

合成受体信号转导有可能赋予过继转移的 T 细胞新功能，从而克服实体瘤治疗中的主要障碍，包括对调理化疗的需要^1,2。在这里，我们设计了具有正交 IL-2 受体胞外域 (ECD) 的嵌合受体，该受体与常见 γ 链 (γ c ) 细胞因子 IL-4、IL-7、IL-9 和受体的胞内域 (ICD ₎融合IL-21 使得正交 IL-2 细胞因子引发相应的 γ _c细胞因子信号。其中，通过嵌合正交 IL-2Rβ-ECD-IL-9R-ICD (o9R) 发出信号的 T 细胞的特点是同时激活 STAT1、STAT3 和 STAT5，并呈现干细胞记忆和效应 T 细胞的特征。与 o2R T 细胞相比，o9R T 细胞在黑色素瘤和胰腺癌的两种顽固性同系小鼠实体瘤模型中具有优异的抗肿瘤功效，并且即使在没有条件性淋巴细胞耗竭的情况下也有效。因此，通过使用嵌合正交细胞因子受体重新利用 IL-9R 信号，T 细胞获得了新的功能，从而提高了对难以治疗的实体瘤的抗肿瘤活性。