小柯机器人

美国国立卫生研究院Warren J. Leonard等研究人员合作发现，一种工程化的IL-2部分激动剂能促进CD8⁺T细胞的干性。相关论文于2021年9月15日在线发表于国际学术期刊《自然》。

研究人员表示，抗原特异性T细胞的适应性转移是癌症免疫治疗的一个重大进展，并在一些患者中取得了良好的临床效果。转移的T细胞数量和它们的分化状态都是决定有效反应的关键因素。T细胞可以通过T细胞受体（TCR）介导的刺激和白细胞介素-2进行扩增，但这可能导致分化为效应性T细胞，降低疗效，而在采用转移前保持更多干细胞样状态是有益的。

研究人员发现，H9T（一种工程化的白细胞介素-2部分激动剂）能促进CD8⁺T细胞的扩增而不驱动终端分化。H9T导致了STAT5信号的改变，并介导了独特的下游转录、表观遗传和代谢程序。此外，H9T处理维持了T细胞转录因子1（TCF-1）的表达，促进了线粒体健康，从而促进了干细胞样状态的维持。此外，用H9T扩增的TCR转基因和嵌合抗原受体修饰的CD8⁺T细胞在黑色素瘤和急性淋巴细胞白血病的小鼠模型中显示出强大的抗肿瘤活性。因此，具有独特性质的细胞因子变体工程是创造具有转化潜力新分子的一种策略。

附：英文原文

Title: An engineered IL-2 partial agonist promotes CD8+ T cell stemness

Author: Mo, Fei, Yu, Zhiya, Li, Peng, Oh, Jangsuk, Spolski, Rosanne, Zhao, Liang, Glassman, Caleb R., Yamamoto, Tori N., Chen, Yun, Golebiowski, Filip M., Hermans, Dalton, Majri-Morrison, Sonia, Picton, Lora K., Liao, Wei, Ren, Min, Zhuang, Xiaoxuan, Mitra, Suman, Lin, Jian-Xin, Gattinoni, Luca, Powell, Jonathan D., Restifo, Nicholas P., Garcia, K. Christopher, Leonard, Warren J.

Issue&Volume: 2021-09-15

Abstract: Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients1. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses2,3. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells4,5 and lower therapeutic efficacy6, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial7. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8+ T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8+ T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential.

DOI: 10.1038/s41586-021-03861-0

Source: https://www.nature.com/articles/s41586-021-03861-0

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