美国纽约大学Iannis Aifantis等研究人员合作发现，应激反应调节因子HSF1调节自然杀伤细胞的抗肿瘤免疫。这一研究成果于2024年9月2日在线发表在国际学术期刊《自然—细胞生物学》上。

研究人员利用热休克因子1（HSF1）激活的小鼠模型和单细胞转录组肿瘤谱分析显示，增强的HSF1活性在自然杀伤（NK）细胞中会削弱细胞毒性、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。这些发现对提高过继性NK细胞治疗的疗效和设计包括NK细胞介导的肿瘤杀伤调节剂的组合策略具有重要意义。

据悉，多种细胞损伤会汇聚到HSF1的激活上，HSF1调节蛋白质毒性应激反应，以维持蛋白质稳态。HSF1在细胞类型和特定环境中以特定方式调节多种基因程序，促进恶性肿瘤的发展。然而，HSF1在肿瘤微环境中的免疫群体中的角色仍不清楚。

附：英文原文

Title: The stress response regulator HSF1 modulates natural killer cell anti-tumour immunity

Author: Hockemeyer, Kathryn, Sakellaropoulos, Theodore, Chen, Xufeng, Ivashkiv, Olha, Sirenko, Maria, Zhou, Hua, Gambi, Giovanni, Battistello, Elena, Avrampou, Kleopatra, Sun, Zhengxi, Guillamot, Maria, Chiriboga, Luis, Jour, George, Dolgalev, Igor, Corrigan, Kate, Bhatt, Kamala, Osman, Iman, Tsirigos, Aristotelis, Kourtis, Nikos, Aifantis, Iannis

Issue&Volume: 2024-09-02

Abstract: 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. Hockemeyer et al. demonstrate that HSF1 activation inhibits cytokine production and cytotoxic activity in NK cells to impair anti-tumour immune responses.

DOI: 10.1038/s41556-024-01490-z

Source: https://www.nature.com/articles/s41556-024-01490-z