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
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引用次数: 0
摘要
热休克因子 1(HSF1)可调控蛋白毒性应激反应,以维持蛋白质平衡。除蛋白毒性应激反应外,HSF1 还以细胞类型和特定环境的方式调控许多基因程序,从而促进恶性肿瘤的发生。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肿瘤转录组图谱分析表明,自然杀伤(NK)细胞中 HSF1 活性的增强会损害细胞毒性、细胞因子的产生和随后的抗肿瘤免疫。从机理上讲,HSF1 直接结合并调节 NK 细胞效应功能关键介质的表达。这项研究表明,HSF1 在肿瘤微环境的应激条件下调节免疫反应。这些发现对提高采用性 NK 细胞疗法的疗效以及设计包括 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。
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.
期刊介绍:
Nature Cell Biology, a prestigious journal, upholds a commitment to publishing papers of the highest quality across all areas of cell biology, with a particular focus on elucidating mechanisms underlying fundamental cell biological processes. The journal's broad scope encompasses various areas of interest, including but not limited to:
-Autophagy
-Cancer biology
-Cell adhesion and migration
-Cell cycle and growth
-Cell death
-Chromatin and epigenetics
-Cytoskeletal dynamics
-Developmental biology
-DNA replication and repair
-Mechanisms of human disease
-Mechanobiology
-Membrane traffic and dynamics
-Metabolism
-Nuclear organization and dynamics
-Organelle biology
-Proteolysis and quality control
-RNA biology
-Signal transduction
-Stem cell biology