Isolated BAP1 Genomic Alteration in Malignant Pleural Mesothelioma Predicts Distinct Immunogenicity with Implications for Immunotherapeutic Response

Abstract

Malignant pleural mesothelioma (MPM), an aggressive cancer of the mesothelial cells lining the pleural cavity, lacks effective treatments. Multiple somatic mutations and copy number losses in tumor suppressor genes (TSGs) BAP1, CDKN2A/B, and NF2 are frequently associated with MPM. The impact of single versus multiple genomic alterations of TSG on MPM biology, the immune tumor microenvironment, clinical outcomes, and treatment responses are unknown. Tumors with genomic alterations in BAP1 alone were associated with a longer overall patient survival rate compared to tumors with CDKN2A/B and/or NF2 alterations with or without BAP1 and formed a distinct immunogenic subtype with altered transcription factor and pathway activity patterns. CDKN2A/B genomic alterations consistently contributed to an adverse clinical outcome. Since the genomic alterations of only BAP1 was associated with the PD-1 therapy response signature and higher LAG3 and VISTA gene expression, it might be a candidate marker for immune checkpoint blockade therapy. Our results on the impact of TSG genotypes on MPM and the correlations between TSG alterations and molecular pathways provide a foundation for developing individualized MPM therapies.

Viral Mimicry Response Is Associated With Clinical Outcome in Pleural Mesothelioma

“… 5 , 7 Pathway-enriched analysis of genes expressed in the clusters revealed, among others, enrichment of reactome antiviral mechanism by ISG in one of the TCGA clusters, and this is confirmed in the epithelioid group of Bueno et al. 5 Patients with this profile have a better clinical outcome 7 , 9 , 15 and BAP1 mutations, 15 consistent with our observations that tumors with high levels of ERVmap_1248 are associated with BAP1 mutations.…”

“…7 A) and is consistent with the TCGA cluster classification where the cluster with the best survival is related with type I IFN signaling and BAP1 mutation is associated with a longer overall patient survival rate. 15 No significant association with histotype was observed ( Supplementary Fig. 7 B).…”

“… 14 In addition to the effects as transcription regulators, the expression of ERV has been recently explored for its property as inducers of viral mimicry response, especially in immunotherapy context, and we and others have observed that expression of interferon-induced genes is associated with clinical outcome in patients with mesothelioma. 9 , 15 …”

Spatial landscape of malignant pleural and peritoneal mesothelioma tumor immune microenvironment

“…The genomic profile of MM reveals a low protein-coding mutation rate, with the most commonly occurring alterations being mutations and deletions of the tumor suppressor genes (TSGs) BRCA1 associated protein-1 ( BAP1 ; located at chromosome band 3p21), neurofibromatosis type 2 ( NF2 ; 22q12), and cyclin-dependent kinase inhibitor 2A and 2B ( CDKN2A/B ; 9p21) 9-14 . Recently, we provided a comprehensive analysis of data on MPM tumors with genomic alteration in one or more of these specific TSGs, which are thought to be critical drivers of MPM pathogenesis 15 . Although alterations of these key TSGs frequently occur in various combinations in a given MM tumor, we showed that alteration of BAP1 alone is associated with a better clinical outcome and an immunotherapy response signature.…”

“…Interestingly, BAP1 alterations have been shown recently to be correlated with perturbed immune signaling in MPeM 16 . Furthermore, MPM tumors with alterations in BAP1 alone showed a distinct pattern of expression of inflammatory tumor microenvironment genes, including activation of interferon signaling and IRF transcription factors (TFs) and high LAG3 (lymphocyte activation gene-3) and VISTA (V-domain Ig suppressor of T cell activation) immune checkpoint expression 15 . LAG3 is expressed on activated T cells and has now become a part of the repertoire of combinatorial immunotherapies available for the treatment of metastatic melanoma 17 .…”