应激反应调节因子 HSF1 调节自然杀伤细胞抗肿瘤免疫。
The stress response regulator HSF1 modulates natural killer cell anti-tumour immunity.
发表日期：2024 Sep 02
作者：
Kathryn Hockemeyer, Theodore Sakellaropoulos, Xufeng Chen, Olha Ivashkiv, Maria Sirenko, Hua Zhou, Giovanni Gambi, Elena Battistello, Kleopatra Avrampou, Zhengxi Sun, Maria Guillamot, Luis Chiriboga, George Jour, Igor Dolgalev, Kate Corrigan, Kamala Bhatt, Iman Osman, Aristotelis Tsirigos, Nikos Kourtis, Iannis Aifantis
来源：
CYTOKINE & GROWTH FACTOR REVIEWS
摘要：
多种细胞损伤集中在热休克因子 1 (HSF1) 的激活上，该因子可调节蛋白毒性应激反应以维持蛋白质稳态。 HSF1 以细胞类型和环境特异性的方式调节蛋白毒性应激反应之外的许多基因程序，以促进恶性肿瘤。然而，HSF1 在肿瘤微环境免疫群体中的作用仍然难以捉摸。在这里，我们利用 HSF1 激活的体内模型和单细胞转录组肿瘤分析来证明自然杀伤 (NK) 细胞中 HSF1 活性的增强会损害细胞毒性、细胞因子产生和随后的抗肿瘤免疫。从机制上讲，HSF1 直接结合并调节 NK 细胞效应功能关键介质的表达。这项工作表明HSF1在肿瘤微环境的应激条件下调节免疫反应。这些发现对于提高过继性 NK 细胞疗法的功效以及设计包括 NK 细胞介导的肿瘤杀伤调节剂在内的组合策略具有重要意义。© 2024。作者，获得 Springer Nature Limited 的独家许可。
Diverse cellular insults converge on activation of the heat shock factor 1 (HSF1), which regulates the proteotoxic stress response to maintain protein homoeostasis. HSF1 regulates numerous gene programmes beyond the proteotoxic stress response in a cell-type- and context-specific manner to promote malignancy. However, the role(s) of HSF1 in immune populations of the tumour microenvironment remain elusive. Here, we leverage an in vivo model of HSF1 activation and single-cell transcriptomic tumour profiling to show that augmented HSF1 activity in natural killer (NK) cells impairs cytotoxicity, cytokine production and subsequent anti-tumour immunity. Mechanistically, HSF1 directly binds and regulates the expression of key mediators of NK cell effector function. This work demonstrates that HSF1 regulates the immune response under the stress conditions of the tumour microenvironment. These findings have important implications for enhancing the efficacy of adoptive NK cell therapies and for designing combinatorial strategies including modulators of NK cell-mediated tumour killing.© 2024. The Author(s), under exclusive licence to Springer Nature Limited.