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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
Damage-associated molecular patterns and sensing receptors based molecular subtypes in malignant pleural mesothelioma
Zheng Liu1, Rui Wan1, Hua Bai1
1State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Objectives:
Malignant pleural mesothelioma (MPM) is characterized as an incredibly aggressive form of cancer with a dismal diagnosis and a dearth of specific biomarkers and therapeutic options. For MPM patients, the effectiveness of immunotherapy may be influenced by damage-associated molecular pattern (DAMP)-induced immunogenic cell death (ICD).The objective of this work is to create a molecular profile associated with DAMPs to categorize MPM patients and predict their prognosis and response to immunotherapy.
Methods:
The RNA-seq of 397 patients (263 patients with clinical data, 57.2% male, 73.0% over 60 yrs.) were gathered from eight public datasets as a training cohort to identify the DAMPs-associated subgroups of MPMs using K-means analysis. Three validation cohorts of patients or murine were established from TCGA and GEO databases. Comparisons were made across each subtype's immune status, gene mutations, survival prognosis, and predicted response to therapy.
Results:
Based on the DAMPs gene expression, MPMs were categorized into two subtypes: the nuclear DAMPs subtype, which is classified by the upregulation of immune-suppressed pathways, and the inflammatory DAMPs subtype, which is distinguished by the enrichment of proinflammatory cytokine signaling. The inflammatory DAMPs subgroup had a better prognosis, while the nuclear DAMPs subgroup exhibited a worse outcome. In validation cohorts, the subtyping system was effectively verified. We further identified the genetic differences between the two DAMPs subtypes. It was projected that the inflammatory DAMPs subtype will respond to immunotherapy more favorably, suggesting that the developed clustering method may be implemented to predict the effectiveness of immunotherapy.
Conclusion:
We constructed a subtyping model based on ICD-associated DAMPs in MPM, which might serve as a signature to gauge the outcomes of immune checkpoint blockades. Our research may aid in the development of innovative immunomodulators as well as the advancement of precision immunotherapy for MPM.
Insights
Researchers identified two subtypes of malignant pleural mesothelioma (MPM) based on damage-associated molecular patterns (DAMPs). The inflammatory DAMPs subtype shows a better prognosis and may respond better to immunotherapy, offering a new approach for cancer treatment.
Area of Science:
- Oncology
- Immunology
- Genomics
Background:
- Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options.
- Immunotherapy effectiveness in MPM may depend on damage-associated molecular pattern (DAMP)-induced immunogenic cell death (ICD).
Purpose of the Study:
- To develop a molecular profile of DAMPs to classify MPM patients.
- To predict prognosis and immunotherapy response in MPM patients based on DAMPs.
Main Methods:
- RNA-sequencing data from 397 MPM patients were analyzed using K-means clustering to identify DAMPs-associated subgroups.
- Three independent validation cohorts were used to confirm the identified subtypes.
- Immune status, gene mutations, survival, and predicted therapy response were compared across subtypes.
Main Results:
- MPMs were classified into two subtypes: nuclear DAMPs (immune-suppressed pathways) and inflammatory DAMPs (proinflammatory cytokine signaling).
- The inflammatory DAMPs subtype demonstrated a better prognosis, while the nuclear DAMPs subtype had a worse outcome.
- The inflammatory DAMPs subtype is predicted to respond more favorably to immunotherapy.
Conclusions:
- A novel subtyping model for MPM based on ICD-associated DAMPs was developed.
- This model can potentially serve as a signature for predicting immune checkpoint blockade outcomes.
- The findings may facilitate the development of novel immunomodulators and advance precision immunotherapy for MPM.
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