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Mutation status of the KMT2 family associated with immune checkpoint inhibitors (ICIs) therapy and implicating

Dong-Xu Wang1, Jun-Yu Long2, Rui-Zhe Li1

  • 1Department of General Surgery, Qilu Hospital, Shandong University, 107 West Wen Hua Road, Jinan, Shandong, 250012, People's Republic of China.

Molecular Cancer
|January 15, 2024
PubMed

Insights

Mutations in histone-lysine N-methyltransferase 2 (KMT2) family genes are linked to improved outcomes with immune checkpoint inhibitor (ICI) therapy. KMT2 mutations correlate with enhanced tumor immunity and a "hot tumor" phenotype, suggesting better ICI response.

Area of Science:

  • Epigenetics and Tumor Immunity
  • Histone Methylation and Cancer Progression
  • Immune Checkpoint Inhibitor (ICI) Therapy Response

Background:

  • Epigenetic regulation, particularly histone methylation by the KMT2 family, is increasingly recognized for its role in tumor immunity and immune tolerance.
  • Histone H3 lysine 4 (H3K4) methylation by KMT2 enzymes influences chromatin structure, impacting tumor progression and immune evasion.
  • The KMT2 family's role in modulating the tumor microenvironment suggests potential implications for response to immune checkpoint inhibitor (ICI) therapy.

Discussion:

  • This study analyzed integrated clinical and bioinformatic data from 2069 patients across 10 cancer types treated with ICI therapy, alongside The Cancer Genome Atlas pan-cancer cohort.
  • The analysis focused on the association between KMT2 family gene mutations and clinical outcomes, including overall survival, progression-free survival, durable clinical benefit, and objective response rate.
  • Tumor microenvironment characteristics were evaluated based on KMT2 mutation status to understand the underlying mechanisms of ICI response.

Key Insights:

  • Patients with KMT2 family gene mutations demonstrated significantly improved overall survival (P < 0.001), progression-free survival (P = 0.002), durable clinical benefit (P < 0.001), and objective response rate (P < 0.001) with ICI therapy.
  • Tumors with KMT2 mutations exhibited enhanced immunogenicity, increased immune cell infiltration, and higher immune cell cytotoxicity, characteristic of a 'hot tumor' phenotype.
  • These findings suggest that KMT2 mutations are associated with a more favorable response to ICI therapy, potentially mediated by an inflamed tumor microenvironment.

Outlook:

  • KMT2 mutations may serve as a predictive biomarker for ICI therapy efficacy across various cancer types.
  • Further research into the specific mechanisms by which KMT2 alterations influence the tumor immune microenvironment is warranted.
  • Targeting KMT2 pathways could potentially enhance responses to immune checkpoint inhibitors in non-responding or partially responding patients.
Keywords:
ICI therapyKMT2 gene familyPan-cancer analysisTumor microenvironment

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