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

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

  • Cell Rep. 2024 Sep 24;43(9):114686. doi: 10.1016/j.celrep.2024.114686.
Ruijie Wang 1,  Chuwen Li 1,  Zhongyi Cheng 2,  Mingyu Li 1,  Jianbo Shi 1,  Zhiyuan Zhang 1,  Shufang Jin 3,  Hailong Ma 4
Affiliations

Affiliations

  • 1 Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; National Center for Stomatology & National Clinical Research Center for Oral Diseases, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China.
  • 2 Jingjie PTM Biolab (Hangzhou), Hangzhou, Zhejiang 310018, China.
  • 3 National Center for Stomatology & National Clinical Research Center for Oral Diseases, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China; Department of Second Dental Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University, Shanghai 200011, China. Electronic address: 72300120147@shsmu.edu.cn.
  • 4 Department of Oral Maxillofacial-Head and Neck Oncology, Shanghai Ninth People's Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China; National Center for Stomatology & National Clinical Research Center for Oral Diseases, Shanghai 200011, China; Shanghai Key Laboratory of Stomatology & Shanghai Research Institute of Stomatology, Shanghai 200011, China. Electronic address: mahl21@sjtu.edu.cn.
PMID: 39216002 DOI: 10.1016/j.celrep.2024.114686
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.

Keywords

CP: Cancer; CP: Metabolism; T cell dysfunction; head and neck squamous cell carcinoma; histone lactylation; interleukin-11; tumor microenvironment.

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