H3K9 lactylation in malignant cells facilitates CD8⁺ T cell dysfunction and poor immunotherapy response.

IF 7.5 1区生物学 Q1 CELL BIOLOGY

Cell reports Pub Date : 2024-09-24 Epub Date: 2024-08-30 DOI:10.1016/j.celrep.2024.114686

Ruijie Wang, Chuwen Li, Zhongyi Cheng, Mingyu Li, Jianbo Shi, Zhiyuan Zhang, Shufang Jin, Hailong Ma

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引用次数: 0

Abstract

Histone lysine lactylation (Kla) is a post-translational modification, and its role in tumor immune escape remains unclear. Here, we find that increased histone lactylation is associated with poor response to immunotherapy in head and neck squamous cell carcinoma (HNSCC). H3K9la is identified as a specific modification site in HNSCC. Using cleavage under targets and tagmentation analyses, interleukin-11 (IL-11) is identified as a downstream regulatory gene of H3K9la. IL-11 transcriptionally activates immune checkpoint genes through JAK2/STAT3 signaling in CD8⁺ T cells. Additionally, IL-11 overexpression promotes tumor progression and CD8⁺ T cell dysfunction in vivo. Moreover, IL11 knockdown reverses lactate-induced CD8⁺ T cell exhaustion, and cholesterol-modified siIL11 restores CD8⁺ T cell killing activity and enhances immunotherapy efficacy. Clinically, H3K9la positively correlates with IL-11 expression and unfavorable immunotherapy responses in patients. This study reveals the crucial role of histone lactylation in immune escape, providing insights into immunotherapy strategies for HNSCC.

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恶性细胞中的 H3K9 乳化促进 CD8+ T 细胞功能障碍和免疫疗法反应不良。

组蛋白赖氨酸乳酰化（Kla）是一种翻译后修饰，它在肿瘤免疫逃逸中的作用尚不清楚。在这里，我们发现组蛋白乳酰化的增加与头颈部鳞状细胞癌（HNSCC）对免疫疗法的不良反应有关。H3K9la被确定为HNSCC中的一个特异性修饰位点。通过目标下裂解和标记分析，白细胞介素-11（IL-11）被确定为 H3K9la 的下游调控基因。IL-11通过CD8+ T细胞中的JAK2/STAT3信号转导转录激活免疫检查点基因。此外，IL-11 的过表达会促进肿瘤进展和体内 CD8+ T 细胞的功能障碍。此外，IL11敲除可逆转乳酸诱导的CD8+ T细胞衰竭，胆固醇修饰的siIL11可恢复CD8+ T细胞的杀伤活性并提高免疫疗法的疗效。在临床上，H3K9la 与 IL-11 的表达和患者不利的免疫治疗反应呈正相关。这项研究揭示了组蛋白乳酰化在免疫逃逸中的关键作用，为HNSCC的免疫治疗策略提供了启示。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.