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Implantation and Monitoring by PET/CT of an Orthotopic Model of Human Pleural Mesothelioma in Athymic Mice
Published on: December 21, 2019
Tumor DNA methylation subtypes predict immunotherapy outcomes in pleural mesothelioma patients in the NIBIT-EPI-MESO
Luana Calabrò1,2,3, Francesca P Caruso4, Alessia Covre5,6
1Department of Translational Medicine, University of Ferrara, Ferrara, Italy.
Abstract:
Pleural mesothelioma (PM) has a poor prognosis and standard therapy with immune checkpoint inhibitors (ICIs) CTLA-4 and PD-1 is still clinically unsatisfying. No predictive biomarkers of ICI efficacy in PM are available yet. In the retrospective multicenter NIBIT-EPI-MESO study, multi-omics analysis of pre-ICI therapy tumor lesions from 91 patients with PM treated in earlier clinical trials or in daily practice identified four PM subsets with progressively increasing global DNA methylation profiles-demethylated, LOW, intermediate and CpG island methylator phenotype (CIMP). These methylation subsets predicted response and survival to ICI therapy. The LOW subset was enriched in responder patients, who had the longest median overall survival and the highest 3-year overall survival rate, and showed a T cell- and B cell-rich immune microenvironment. Conversely, the CIMP subtype was enriched in nonresponder patients with the shortest median overall survival and overall survival, along with a depleted immune microenvironment. A methylation-based probabilistic decision-making classification tool to predict the outcome of ICI treatment in patients with PM was developed.
Insights
DNA methylation profiles in pleural mesothelioma (PM) predict response to immune checkpoint inhibitors (ICIs). The LOW methylation subset indicates better survival and a robust immune microenvironment, unlike the CIMP subtype.
Area of Science:
- Oncology
- Immunotherapy
- Epigenetics
Background:
- Pleural mesothelioma (PM) has a poor prognosis, and current immune checkpoint inhibitor (ICI) therapies (CTLA-4, PD-1) offer limited clinical benefit.
- Biomarkers to predict ICI efficacy in PM are currently lacking.
Purpose of the Study:
- To identify predictive biomarkers for ICI therapy response in pleural mesothelioma.
- To investigate the association between DNA methylation profiles and ICI treatment outcomes in PM patients.
Main Methods:
- Retrospective multicenter study (NIBIT-EPI-MESO) involving 91 PM patients treated with ICIs.
- Multi-omics analysis of pre-ICI tumor lesions to characterize DNA methylation profiles.
- Identification of four PM subsets based on global DNA methylation: demethylated, LOW, intermediate, and CIMP.
Main Results:
- DNA methylation subsets significantly predicted response and survival to ICI therapy.
- The LOW methylation subset was associated with higher response rates, longer median overall survival, and a T/B cell-rich immune microenvironment.
- The CIMP subtype correlated with non-response, shorter survival, and a depleted immune microenvironment.
Conclusions:
- Global DNA methylation profiles serve as predictive biomarkers for ICI efficacy in pleural mesothelioma.
- A methylation-based classification tool was developed to predict ICI treatment outcomes in PM patients.
- Understanding methylation-driven immune microenvironments can guide future therapeutic strategies.
