Department of Pathology, NYU Grossman School of Medicine, New York, NY, USA.
Laura & Isaac Perlmutter Cancer Center, NYU Grossman School of Medicine, New York, NY, USA.
Nat Cell Biol. 2024 Oct;26(10):1734-1744. doi: 10.1038/s41556-024-01490-z. Epub 2024 Sep 2.
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.
多种细胞损伤可集中激活热休克因子 1（HSF1），后者调节蛋白质毒性应激反应以维持蛋白质的体内平衡。HSF1 通过细胞类型和特定的上下文以多种方式调节许多超出蛋白质毒性应激反应的基因程序，从而促进恶性肿瘤的发生。然而，HSF1 在肿瘤微环境的免疫群体中的作用仍不清楚。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，表明 NK 细胞中增强的 HSF1 活性会损害细胞毒性、细胞因子产生以及随后的抗肿瘤免疫。从机制上讲，HSF1 直接结合并调节 NK 细胞效应功能的关键介质的表达。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。这些发现对于增强过继性 NK 细胞疗法的疗效以及设计包括增强 NK 细胞介导的肿瘤杀伤的调节剂的组合策略具有重要意义。
