Signatures of H3K4me3 modification predict cancer immunotherapy response and identify a new immune checkpoint-SLAMF9

Tao Fan ¹, Chu Xiao ¹, Ziqin Deng ¹

⁰Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.

Respiratory Research +

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January 15, 2025

View abstract on PubMed

Summary

This study introduces a new H3K4me3 risk score to predict cancer immunotherapy response. This biomarker system, linked to tumor immune infiltration, shows promise in identifying patients likely to benefit from treatments like ICB therapy.

Area Of Science

Epigenetics and Cancer Immunology
Molecular Oncology

Background

H3 lysine 4 trimethylation (H3K4me3) is a key epigenetic regulator of gene transcription in health and disease.
The precise role of H3K4me3 modification in anti-tumor immunity remains incompletely understood.
Understanding these regulatory mechanisms is crucial for developing novel cancer therapies.

Purpose Of The Study

To investigate the relationship between H3K4me3 modification and anti-tumor immunity.
To develop a predictive biomarker system for immunotherapy response based on H3K4me3-related genes.
To explore the potential of SLAMF9 as a therapeutic target in cancer immunotherapy.

Main Methods

Identified 72 prognostic genes in lung adenocarcinoma (LUAD) correlated with 27 H3K4me3 regulators.
Constructed three H3K4me3 modification patterns and a H3K4me3 risk score (H3K4me3-RS) using principal component analysis (PCA).
Validated H3K4me3-RS using deep learning on large cancer and immunotherapy cohorts, and employed a mice melanoma model.

Main Results

H3K4me3 modification patterns correlated with distinct tumor immune infiltration profiles.
H3K4me3-RS demonstrated significant correlation with cancer immune tolerance and sensitivity across multiple cancer types.
H3K4me3-RS accurately predicted immunotherapy response, identifying SLAMF9 as an immunosuppressive gene associated with resistance.
Slamf9 knockdown in a mouse model reduced tumor progression and enhanced anti-CTLA-4/anti-PD-L1 therapy efficacy.

Conclusions

The developed H3K4me3 risk score system serves as a novel biomarker for predicting tumor immunotherapy response.
SLAMF9 plays a critical role in immune evasion and immunotherapy resistance, suggesting its potential as a therapeutic target.
This research provides a preclinical basis for targeting SLAMF9 to enhance cancer immunity and treatment outcomes.

Related Concept Videos

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.