BAP1 Deficiency Inflames the Tumor Immune Microenvironment and Is a Candidate Biomarker for Immunotherapy Response in Malignant Pleural Mesothelioma.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:38715965", "kind": "science-record", "revision": 5, "content_hash": "sha256:98494bca40935a6b45faacabf1c3f7d76c678cece3033108badc4ed7c45e825c", "created_at": "2026-11-01T19:20:41Z", "updated_at": "2026-11-01T22:54:16Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "BAP1 Deficiency Inflames the Tumor Immune Microenvironment and Is a Candidate Biomarker for Immunotherapy Response in Malignant Pleural Mesothelioma.", "doi": "10.1016/j.jtocrr.2024.100672", "pmid": "38715965", "authors": ["Duo Xu", "Yanyun Gao", "Haitang Yang", "Marc Spils", "Thomas M Marti", "Tereza Losmanová", "Min Su", "Wenxiang Wang", "Qinghua Zhou", "Patrick Dorn", "Yongqian Shu", "Ren-Wang Peng"], "journal": "JTO clinical and research reports", "year": 2024, "abstract": "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.\nMethods: We performed multiscale integrative analyses of published primary tumor data set from The Cancer Genome Atlas (TCGA) and the French cohort E-MTAB-1719 to unravel the tumor immune microenvironment 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 patients with MPM using immunohistochemistry and multiplex immunohistochemistry.\nResults: We revealed that BAP1 deficiency enriches immune-associated pathways in MPM, leading to increased mRNA signatures of interferon alfa/gamma response, activating 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 tumor immune microenvironment 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 revealed that BAP1-proficient MPM is associated with a hyperactive mitogen-activated protein kinase (MAPK) pathway and may benefit from treatment with MEK inhibitors (MEKis).\nConclusion: 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.", "claims": [{"id": "claim-method", "statement": "The empirical Bayesian approach of the limma R package was applied to identify differentially expressed genes (DEGs) from the gene expression profile between BAP1-deficient and BAP1-proficient subgroups.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38715965", "locator": "sections[4] \"Identification of DEGs and Pathway Enrichment Analysis\" paragraph 2", "quote": "The empirical Bayesian approach of the limma R package was applied to identify differentially expressed genes (DEGs) from the gene expression profile between BAP1-deficient and BAP1-proficient subgroups."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The RNA sequencing (RNA-seq) data (FPKM value), copy number variants (CNVs), genomic alterations, and clinical information of the MPM patient cohorts from two published data sets TCGA and the French MPM patient cohort (under accession code E-MTAB-1719), herein referred to as E-MTAB-1719 cohort,2,20 were downloaded from the UCSC Xena (https://xenabrowser.net/datapages/).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:38715965", "locator": "sections[3] \"Data Retrieval and Processing\" paragraph 2", "quote": "The RNA sequencing (RNA-seq) data (FPKM value), copy number variants (CNVs), genomic alterations, and clinical information of the MPM patient cohorts from two published data sets TCGA and the French MPM patient cohort (under accession code E-MTAB-1719), herein referred to as E-MTAB-1719 cohort,2,20 were downloaded from the UCSC Xena (https://xenabrowser.net/datapages/)."}], "state": "complete"}, {"id": "claim-target-result", "statement": "BAP1 deficiency enriches immune-associated pathways and an inflammatory tumor immune microenvironment in MPM, whereas BAP1-proficient MPM exhibits hyperactive MAPK signaling and may benefit from MEK inhibitors.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:38715965", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "We revealed that BAP1 deficiency enriches immune-associated pathways in MPM, leading to increased mRNA signatures of interferon alfa/gamma response, activating dendritic cells, immune checkpoint receptors, and T-cell inflammation."}, {"asset": "source:pmid:38715965", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "Finally, we revealed that BAP1-proficient MPM is associated with a hyperactive mitogen-activated protein kinase (MAPK) pathway and may benefit from treatment with MEK inhibitors (MEKis)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "BAP1 deficiency enriches immune-associated pathways and an inflammatory tumor immune microenvironment in MPM, whereas BAP1-proficient MPM exhibits hyperactive MAPK signaling and may benefit from MEK inhibitors.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:38715965"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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