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S Hijazo-Pechero

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    MA12 - New Frontiers from Pathology to Genomics (ID 138)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Mesothelioma
    • Presentations: 1
    • Now Available
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      MA12.07 - Integrative Transcriptome Analysis of Malignant Pleural Mesothelioma Reveals a Clinically-Relevant Immune-Based Classification (Now Available) (ID 1680)

      14:00 - 15:30  |  Author(s): S Hijazo-Pechero

      • Abstract
      • Presentation
      • Slides


      Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lining of the lungs. Immune checkpoint inhibitors in MPM have not been extremely successful, likely due to a poor identification of suitable candidate patients for the therapy. The aims of this study were: to identify immune fractions associated with clinical outcome and classify MPM samples based on their immune contexture; to characterize the immune-based groups at the genomic and transcriptomic levels; and to identify potential therapeutic strategies for each group.


      Seven gene-expression datasets of MPM were used to assess the immune microenvironment of 516 samples. The abundance of 20 immune fractions in each sample was inferred using Gene Set Variation Analysis. Identification of clinically-relevant fractions was performed with Cox Proportional-Hazards Models adjusted for age, stage, sex, and tumor histology.


      T-Helper 2 (TH2, HR=2.14, p=1.5x10-4) and cytotoxic T cells (CTC; HR=0.57, p=9.1x10-3) were found to be consistently associated with overall survival in multiple datasets. Three immune clusters (IG) were subsequently defined based on TH2 and CTC immune infiltration levels: IG1 (54.5% of samples) was characterized by high TH2 and low CTC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2 and high CTC levels. This classification was associated with overall survival independently of tumor histology, with an improving survival from IG1 to IG3 (HRIG2=0.52 (0.39–0.69); HRIG3=0.32 (0.19–0.53); p=8.4x10-8).


      IG3 was significantly enriched in epithelioid tumors (90% IG3 vs. 62% IG1, p=0.001) and patients were younger compared to the other groups (60 years IG3 vs. 66 years IG1, p=0.021). These groups showed differential molecular profiles, with IG1 enriched for CDKN2A and IFN-related genes deletions. At the transcriptional level, IG1 samples showed upregulation of proliferation and DNA repair-related gene-sets, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, integration of gene expression with functional signatures of in vitro drug response showed that IG3 patients are more likely to respond to immune checkpoint inhibitors, while IG1 patients could be more sensitive to PARP inhibitors.


      Analysis of publicly available MPM transcriptome data reveals three major immune-based groups, based on TH2 and CTC composition. These clusters are associated with distinct genomic profiles and clinical outcome. Further validation of this classification is warranted in an independent cohort of MPM.

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