Damage-associated molecular patterns and sensing receptors based molecular subtypes in malignant pleural mesothelioma and implications for immunotherapy

Our plain-English summary of Damage-associated molecular patterns and sensing receptors based molecular subtypes in malignant pleural mesothelioma and implications for immunotherapy, by Z. Liu, R. Wan, H. Bai, et al (Frontiers in Immunology, 2023).

The study

• Authors: Z. Liu, R. Wan, H. Bai, J. Wang
• Journal: Frontiers in Immunology
• Published: 2023;14:1104560
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

Copyright © 2023 Liu, Wan, Bai and Wang.

In plain English

This computer-based study analyzed public tumor gene-activity data from people with malignant pleural mesothelioma. The authors sorted tumors from 397 patients in eight public datasets by the activity of 25 genes linked to 'damage-associated molecular patterns' (DAMPs), molecules involved in immune-provoking cell death. The tumors fell into two subtypes: 230 'inflammatory' and 167 'nuclear'. Only 63 of these patients had survival data; among them, median overall survival was 23.0 months for the inflammatory subtype and 14.0 months for the nuclear subtype. In 86 patients from a separate public database (TCGA), the figures were 20.7 versus 15.1 months. Asbestos exposure was recorded for some training patients and did not differ significantly between subtypes. In 48 mice given two immunotherapy drugs, tumors responded in 100% of the inflammatory subtype versus 7.7% of the nuclear subtype. Among 10 patients given a PD-1 inhibitor, response rates (57.1% vs 0%) did not differ significantly, but disease control (85.7% vs 0%) did. The authors concluded the subtypes may help predict immunotherapy benefit, and called for larger studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Bioinformatic (computer-based) analysis of publicly available gene expression and genomic datasets, using clustering to define tumor subtypes, with validation in separate patient and mouse datasets
• Who was studied: Training cohort: 397 malignant pleural mesothelioma patients from eight GEO and ArrayExpress datasets (57.2% male; 63 with overall survival data). Validation cohorts: 86 patients from TCGA-MESO (82.5% male), two mouse datasets, and one GEO dataset (GSE99070) of patients treated with immunotherapy. Study dates were not given.
• Exposure: Tumor expression of 25 DAMPs-related genes, used to group tumors. Asbestos exposure status was recorded for some training-cohort patients but was not the focus of the study.
• Main results:
  • In the training cohort, 167 of 397 patients were classified into the nuclear DAMPs subtype and 230 into the inflammatory DAMPs subtype.
  • In the training cohort, overall survival data were available for 63 of the 397 patients. Among these patients, median overall survival was 23.0 months in the inflammatory DAMPs subtype versus 14.0 months in the nuclear DAMPs subtype, P=0.021.
  • TCGA validation cohort (86 patients with overall survival data): median overall survival was 20.7 months in the inflammatory DAMPs subtype versus 15.1 months in the nuclear DAMPs subtype, P=0.019.
  • Asbestos exposure in the training cohort (Table 1): 44 exposed (28 inflammatory, 16 nuclear), 13 not exposed (7, 6), and 3 probably exposed (2, 1). There was no significant difference between subtypes (P greater than 0.05).
  • TCGA cohort: CD8A and CTLA-4 expression were higher in the inflammatory subtype. PD-1 and PD-L1 expression did not differ significantly between subtypes.
  • In 48 mesothelioma mice given a PD-L1 inhibitor plus a CTLA-4 inhibitor, the response rate was 100% in the inflammatory subtype versus 7.7% in the nuclear subtype, P less than 0.001.
  • In 10 mesothelioma patients given a PD-1 inhibitor alone, the response rate was 57.1% (inflammatory) versus 0% (nuclear), P=0.2, which was not statistically significant. The disease control rate was 85.7% versus 0%, P=0.033.
  • TCGA cohort: copy number deletions were more frequent in the nuclear DAMPs subtype than in the inflammatory subtype (P less than 0.001). Differences in TTN mutations (21.6% vs 14.3%, P=0.73) and TP53 mutations were not statistically significant.
• The authors' conclusion: The authors concluded that two DAMPs-based molecular subtypes of malignant pleural mesothelioma differ in signaling pathways and immune status, with differing prognoses and immune checkpoint inhibitor efficacy. They also concluded that the method may help identify patients likely to benefit from these drugs.
• Limitations the authors state:
  • Some genes in the planned gene list had to be excluded because of limitations of microarray data.
  • Sequencing data on mesothelioma patients treated with immune checkpoint inhibitors were insufficient, so mouse models of a single strain and cell line were used for additional validation.
  • In patients, the difference in response rate to PD-1 inhibitors between subtypes was not statistically significant. The authors attributed this probably to small sample size or limited single-agent efficacy, and they called for larger cohorts or clinical trials.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunotherapy, Biomarker, Prognosis, Cytokine.

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