Integrative transcriptome analysis of malignant pleural mesothelioma reveals a clinically relevant immune-based classification

Background. Malignant pleural mesothelioma (MPM) is a rare and aggressive neoplasia affecting the lung mesothelium. Immune checkpoint inhibitors (ICI) in MPM have not been extremely successful, likely due to poor identification of suitable candidate patients for the therapy. We aimed to identify cellular immune fractions associated with clinical outcome and classify MPM patients based on their immune contexture. For each defined group, we sought for molecular specificities that could help further define our MPM classification at the genomic and transcriptomic level, as well as identify differential therapeutic strategies based on transcriptional signatures predictive of drug response. Methods. The abundance of 20 immune cell fractions in 516 MPM samples from 7 gene expression datasets 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. Immune-based groups were identified using unsupervised classification. Results. T-Helper 2 (TH2) and cytotoxic T (TC) cells were found to be consistently associated with overall survival. Three immune clusters (IG) were subsequently defined based on TH2 and TC immune infiltration levels: IG1 (54.5%) was characterized by high TH2 and low TC levels, IG2 (37%) had either low or high levels of both fractions, and IG3 (8.5%) was defined by low TH2and high TC levels. IG1 and IG3 groups were associated with worse and better overall survival, respectively. The three 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 signatures, while IG3 samples presented upregulation of immune and inflammation-related pathways. Finally, the integration of gene expression with functional signatures of drug response showed that IG3 patients might be more likely to respond to ICI, while IG1 patients could be more sensitive to PARP inhibitors. Conclusions. This study identifies a novel immune-based signature with potential clinical relevance based on TH2 and TC levels, unveiling a fraction of MPM patients with better prognosis and who might benefit from immune-based therapies. Genomic and transcriptomic specificities of the different groups could be used to tailor potential therapies in the future.