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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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  5. Predictive And Prognostic Markers
  6. 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

Ruijie Wang1, Chuwen Li1, Zhongyi Cheng2

  • 1Department 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.

Cell Reports
|August 31, 2024

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View abstract on PubMed

Summary
This summary is machine-generated.

Histone lactylation (Kla) in head and neck cancer predicts poor immunotherapy response. Targeting interleukin-11 (IL-11) can reverse immune suppression and improve treatment outcomes.

Area of Science:

  • Oncology
  • Immunology
  • Epigenetics

Background:

  • Histone lysine lactylation (Kla) is an emerging post-translational modification.
  • The role of Kla in tumor immune escape is not well understood.
  • Head and neck squamous cell carcinoma (HNSCC) often shows resistance to immunotherapy.

Purpose of the Study:

  • To investigate the role of histone lactylation in HNSCC immune escape.
  • To identify specific lactylation sites and their downstream targets.
  • To explore potential therapeutic strategies targeting lactylation for improved immunotherapy.

Main Methods:

  • Analysis of histone lactylation in HNSCC patient samples.
  • Identification of specific lactylation sites (H3K9la) and downstream genes (IL-11) using CUT&Tag.
Keywords:
CP: CancerCP: MetabolismT cell dysfunctionhead and neck squamous cell carcinoma

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  • Investigation of IL-11 signaling pathways (JAK2/STAT3) in CD8+ T cells.
  • In vivo studies using IL11 knockdown and cholesterol-modified siIL11.
  • Main Results:

    • Increased histone lactylation, specifically H3K9la, correlates with poor immunotherapy response in HNSCC.
    • H3K9la directly regulates Interleukin-11 (IL-11) transcription.
    • IL-11 activates immune checkpoint genes in CD8+ T cells via JAK2/STAT3 signaling, promoting tumor progression and T cell dysfunction.
    • IL11 knockdown and cholesterol-modified siIL11 reversed immune suppression and enhanced immunotherapy efficacy in vivo.

    Conclusions:

    • Histone lactylation, particularly H3K9la, is a key driver of immune escape in HNSCC.
    • The H3K9la-IL-11-JAK2/STAT3 axis represents a novel mechanism of immune suppression.
    • Targeting IL-11 offers a promising strategy to overcome immunotherapy resistance in HNSCC.
    histone lactylation
    interleukin-11
    tumor microenvironment