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Updated: May 10, 2025
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and
Jiaxin Wen1, Yanfeng Wang2, Song Wang3
1Department of Thoracic Surgery, Chinese PLA General Hospital, Beijing, 100853, China.
Background:
Integration of immune checkpoint inhibitors (ICIs) with non-immune therapies relies on identifying combinatorial biomarkers, which are essential for patient stratification and personalized treatment.
Methods:
We analyzed genomic and transcriptomic data from pretreatment tumor samples of 342 melanoma patients treated with ICIs to identify mutations and expression signatures associated with ICI response and survival. External validation and mechanistic exploratory analyses were conducted in two additional datasets to assess generalizability.
Results:
Responders were more likely to have received anti-PD-1 therapy rather than anti-CTLA-4 and exhibited a higher tumor mutation burden (both P < 0.001). Mutations in the dynein axonemal heavy chain (DNAH) family genes, specifically DNAH2 (P = 0.03), DNAH6 (P < 0.001), and DNAH9 (P < 0.01), were enriched in responders. The combined mutational status of DNAH 2/6/9 effectively stratified patients by progression-free survival (hazard ratio [HR]: 0.69; 95% confidence interval [CI] 0.51-0.92; P = 0.013) and overall survival (HR: 0.58; 95% CI 0.43-0.78; P < 0.001), with consistent association observed in the validation cohort (HR: 0.28; 95% CI 0.12-0.61; P < 0.001). DNAH-altered melanomas exhibited upregulation of chemokine signaling, cytokine-cytokine receptor interaction, and cell cycle-related pathways, along with elevated expression of immune-related signatures in interferon signaling, cytolytic activity, T cell function, and immune checkpoints. Using LASSO logistic regression, we identified a 26-gene composite signature predictive of clinical response, achieving an area under the curve (AUC) of 0.880 (95% CI 0.825-0.936) in the training dataset and 0.725 (95% CI 0.595-0.856) in the testing dataset. High-risk patients, stratified by the expression levels of a 13-gene signature, demonstrated significantly shorter overall survival in both datasets (HR: 3.35; P < 0.001; HR: 2.93; P = 0.002).
Conclusions:
This analysis identified potential molecular determinants of response and survival to ICI treatment. Insights from melanoma biomarker research hold significant promise for translation into other malignancies, guiding individualized anti-tumor immunotherapy.
Insights
New research identifies dynein axonemal heavy chain (DNAH) gene mutations as key biomarkers for predicting response to immune checkpoint inhibitors (ICIs) in melanoma patients. These findings enhance patient stratification and personalized immunotherapy strategies.
Area of Science:
- Genomics and Transcriptomics in Oncology
- Immunotherapy Biomarker Discovery
- Melanoma Treatment Response
Background:
- Personalized cancer treatment necessitates identifying biomarkers for patient stratification in immunotherapy.
- Immune checkpoint inhibitors (ICIs) are a cornerstone of modern cancer therapy, but response varies significantly among patients.
- Combinatorial biomarkers are crucial for optimizing ICI efficacy when integrated with other therapeutic modalities.
Purpose of the Study:
- To identify genomic and transcriptomic signatures associated with response and survival in melanoma patients treated with ICIs.
- To evaluate the predictive and prognostic value of identified biomarkers for ICI therapy.
- To explore the molecular mechanisms underlying ICI response in melanoma.
Main Methods:
- Analysis of genomic and transcriptomic data from 342 melanoma patients treated with ICIs.
- Identification of mutations and expression signatures correlated with ICI response and survival.
- External validation in two independent datasets and mechanistic exploratory analyses.
Main Results:
- Mutations in dynein axonemal heavy chain (DNAH) genes (DNAH2, DNAH6, DNAH9) were significantly enriched in ICI responders.
- The combined mutational status of DNAH 2/6/9 effectively stratified patients by progression-free and overall survival.
- A 26-gene composite signature predicted clinical response (AUC=0.880), and a 13-gene signature identified high-risk patients with shorter survival.
Conclusions:
- Dynein axonemal heavy chain (DNAH) gene mutations represent potential molecular determinants of ICI response and survival in melanoma.
- These findings offer insights for developing novel biomarkers to guide individualized anti-tumor immunotherapy.
- The identified biomarkers hold promise for translation into clinical practice for melanoma and potentially other malignancies.
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