Department of Radiation Oncology, David Geffen School of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.
Nature. 2022 Jul;607(7918):360-365. doi: 10.1038/s41586-022-04801-2. Epub 2022 Jun 8.
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. 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) cytokines IL-4, IL-7, IL-9 and IL-21 such that the orthogonal IL-2 cytokine elicits the corresponding γ 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为过继转移的 T 细胞赋予新的功能,克服实体瘤治疗中的主要障碍,包括对条件化疗的需求。在这里,我们设计了嵌合受体,它们具有正交的白细胞介素 2 受体细胞外结构域 (ECD) 与白细胞介素 4、白细胞介素 7、白细胞介素 9 和白细胞介素 21 的共同 γ 链 (γ) 细胞因子受体的细胞内结构域 (ICD) 融合,使得正交白细胞介素 2 细胞因子引发相应的 γ 细胞因子信号。在这些细胞因子中,通过嵌合正交白细胞介素 2Rβ-ECD-白细胞介素 9R-ICD(o9R) 信号转导的 T 细胞的特征是同时激活 STAT1、STAT3 和 STAT5,并具有干细胞记忆和效应 T 细胞的特征。与 o2R T 细胞相比,o9R T 细胞在两种难以治疗的黑色素瘤和胰腺癌同源小鼠实体瘤模型中具有更好的抗肿瘤疗效,即使在没有条件性淋巴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白细胞介素 9R 信号转导,T 细胞获得新的功能,从而提高了难以治疗的实体瘤的抗肿瘤活性。
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