Isolated BAP1 loss in malignant pleural mesothelioma predicts immunogenicity with implications for immunotherapeutic response

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 associated with MPM. The impact of single versus multiple losses of TSG on MPM biology, the immune tumor microenvironment, clinical outcomes, and treatment responses are unknown. Tumors with 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 loss consistently contributed to an adverse clinical outcome. Since the loss of only BAP1 was associated with the PD-1 therapy response signature and higher LAG3 and VISTA gene expression, it is a candidate 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 MPM therapies.