BAP1 deficiency inflames the tumor immune microenvironment and is a candidate biomarker for immunotherapy response in malignant pleural mesothelioma

Introduction Malignant pleural mesothelioma (MPM) is a rare and universally lethal malignancy with limited treatment options. Immunotherapy with immune checkpoint inhibitors (ICIs) has recently been approved for unresectable MPM, but response to ICIs is heterogeneous and reliable biomarkers for prospective selection of appropriate subpopulations likely to benefit from ICIs remain elusive. Methods We performed multiscale integrative analyses of published primary tumor dataset from The Cancer Genome Atlas (TCGA) and the French cohort E-MTAB-1719 to unravel the tumor immune microenvironment (TIME) of MPM deficient in BAP1, one of the most frequently mutated tumor suppressor genes (TSGs) in the disease. The molecular profiling results were validated in independent cohorts of MPM patients using immunohistochemistry (IHC) and multiplex IHC. Results We showed that BAP1 deficiency enriches immune-associated pathways in MPM, leading to increased mRNA signatures of interferon α/γ response, activated dendritic cells, immune checkpoint receptors and T-cell inflammation. This finding was confirmed in independent patient cohorts, where MPM tumors with low BAP1 levels are associated with an inflammatory TIME characterized by increased exhausted precursor T-cells and macrophages, but decreased myeloid-derived suppressor cells (MDSCs). In addition, BAP1low MPM cells are in close proximity to T cells and therefore can potentially be targeted with ICIs. Finally, we showed that BAP1-proficient MPM is associated with a hyperactive mitogen-activated protein kinase (MAPK) pathway and may benefit from treatment with MEK inhibitors (MEKi). Conclusion Our results suggest that BAP1 plays an immunomodulatory role in MPM and that BAP1-deficient MPM may benefit from immunotherapy, which merits further clinical investigation.