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

Abstract

BackgroundMalignant 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 patients with MPM 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.MethodsThe 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 defined based on the identified fractions.ResultsT-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 TH2 and high TC levels. IG1 and IG3 groups were associated with worse and better overall survival, respectively. While no differential genomic alterations were identified among immune groups, 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.ConclusionsThis study identifies a novel immune-based signature with potential clinical relevance based on TH2 and TC levels, unveiling a fraction of patients with MPM with better prognosis and who might benefit from immune-based therapies. Molecular specificities of the different groups might be used to tailor specific potential therapies in the future.

Pathological Characterization of Tumor Immune Microenvironment (TIME) in Malignant Pleural Mesothelioma

“…A recent study by Alay and coworkers, performing an integrative transcriptome analysis on a publicly available dataset of 516 MPMs, revealed a clinically relevant immune-based classification based on CD4+ T-helper 2 (TH2) and CD8+ cytotoxic T cells, that were found to be consistently associated with better overall survival [ 83 ].…”

“…The above-mentioned integrative transcriptome analysis of MPM [ 83 ] revealed a clinically relevant immune-based classification of the same, identifying three immune groups (IG1–IG3) that represent different immune infiltration patterns and are associated with distinct survival outcomes. The group with the shortest overall survival (IG1) represented more than 50% of cases, whereas the IG3 group, having the best prognosis, accounted for 8.5% of cases only.…”

Oncological Frontiers in the Treatment of Malignant Pleural Mesothelioma

“…In the above-mentioned study [ 35 ] carried out by Pasello et al, the biphasic/sarcomatoid histotype was characterized by higher infiltration of CD8+ T lymphocytes and CD68+ macrophages and also by higher PD-L1 expression; these features, which are markers of aggressiveness, are associated with a lower response to chemotherapy but may be the reason why immunotherapy works better [ 17 ]. Similarly, Alay et al analyzed a large collection ( n = 516) of MPM and identified three subgroups according to the relative infiltration of cytotoxic T cells and T-helper 2 cells; the third group (high levels of cytotoxic T cells and low levels of T-helper2 cells) was characterized by an inflamed gene signature and by a better prognosis; the authors also speculated that this subgroup might show better response to immunotherapy [ 36 ].…”

“…The 6-, 12-, and 24-month OS rates were 87.2%, 70.4%, and 44.2%, respectively, while the corresponding PFS rates were 69.1%, 16.4%, and 10.9%. The median PFS was 6.7 months [ 36 ]. An international world-wide phase III randomized study (DR3AM) with this combination is currently ongoing, and results are expected in 2024 (Clinicaltrials.gov no.…”

“…Germline mutations in BAP1 have been identified in families with “BAP1 cancer syndrome”, characterized by the predisposition to developing benign atypical melanocytic lesions, uveal melanomas, and MPM. Additionally, BAP1 somatic mutations/inactivation have been also frequently found in sporadic epithelioid MPM (57–63%) and have been associated with a better response to platinum-based chemotherapy [ 36 , 37 , 41 , 42 ]. Similar to BRCA1/2-deficient cancers, mutation in the BAP1 gene leads to homologous recombination-deficient (HRD) tumors and increases the reliance on poly ADP ribose polymerase (PARP)-mediated DNA repair pathways; therefore, PARP1/2 inhibitors can induce synthetic lethality in MPM.…”