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

SIMPLE SUMMARY: Malignant Pleural Mesothelioma (MPM) is a highly aggressive, therapy-resistant cancer with a well-established inflammatory etiology and has no cure. Immune checkpoint inhibition (ICI) therapy has shifted treatment paradigms in many types of cancers, and recent clinical data have shown promise for improving MPM treatment. However, response to ICI therapy has been neither uniform nor predictable. The genomic landscape of MPM is primarily characterized by genomic alterations in tumor suppressor genes (TSGs) (~70%), particularly BAP1, CDKN2A/B and NF2. The impact of an isolated TSG genomic alteration versus multiple concurrent TSG alterations on clinical outcome, treatment response and MPM biology and the immune tumor microenvironment are unclear. Here, we showed the effect of TSG alteration combinations on clinical outcome, therapeutic response, and molecular pathways in MPM. For example, tumors with alterations in BAP1 alone were (a) associated with a longer overall patient survival rate compared to tumors with CDKN2A/B and/or NF2 alterations with or without BAP1 and (b) comprised a distinct immunogenic subtype with altered transcription factor and pathway activity patterns. 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.