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

Our plain-English summary of BAP1 Deficiency Inflames the Tumor Immune Microenvironment and Is a Candidate Biomarker for Immunotherapy Response in Malignant Pleural Mesothelioma, by D. Xu, Y. Gao, H. Yang, et al (JTO Clinical and Research Reports, 2024).

The study

• Authors: D. Xu, Y. Gao, H. Yang, M. Spils, T.M. Marti, T. Losmanová, M. Su, W. Wang, Q. Zhou, P. Dorn, Y. Shu, R.W. Peng
• Journal: JTO Clinical and Research Reports
• Published: 2024;5(5):100672
• Cited by: 25 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

Methods: 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.

Results: 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).

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.

© 2024 The Authors.

In plain English

This retrospective study examined how BAP1 deficiency (gene deletion or mutation) and low BAP1 protein relate to the immune environment of malignant pleural mesothelioma. The authors reanalyzed published data from The Cancer Genome Atlas (87 tumors) and a French cohort, and stained tissue from Nanjing (17 patients) and Bern (98 patients). Asbestos exposure was not studied. BAP1-deficient tumors showed more immune-response gene activity and higher expression of checkpoint genes PD-L1, PD-1 and LAG3. In tissue, low-BAP1 tumors had significantly more CD163-positive macrophages, no significant difference in CD8-positive T cells, fewer CD14-positive suppressor cells, and T cells lying closer to tumor cells. Among 82 Bern patients, those in the lowest 30% for BAP1 protein lived significantly longer than those in the highest 30% (31.9 versus 17.1 months). In two mouse data sets, the main text reports lower Bap1 in tumors responding to checkpoint inhibitors, but a figure caption says the opposite. The authors concluded that BAP1 status is a candidate biomarker for immunotherapy response needing clinical study. They noted the analysis was largely correlational and the patients had not received immunotherapy.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective analysis of published tumor gene data (TCGA and the French E-MTAB-1719 cohort), checked with tissue staining (immunohistochemistry and multiplex immunohistochemistry) in two hospital cohorts. It also used gene data from immunotherapy-treated mice and drug tests on cell lines.
• Who was studied: Tumors from patients with malignant pleural mesothelioma: TCGA (n = 87) and E-MTAB-1719 (n = 33) data sets; a Nanjing cohort of 17 patients operated on 2011 to 2020; and a Bern cohort of 98 patients with resected tumors 2003 to 2017. Of the Bern patients, 82 were used in the survival analysis.
• Exposure: Not an asbestos exposure study. Tumors were compared by BAP1 status. In the data sets this meant genetic deficiency (homozygous deletion or mutation); in the tissue cohorts it meant low versus high BAP1 protein on staining.
• Main results:
  • In TCGA tumors, immune response pathways (e.g., interferon alpha/gamma response) were enriched in BAP1-deficient tumors compared with BAP1-proficient tumors.
  • In the Bern cohort, the survival comparison used only the lowest 30% and highest 30% of BAP1 protein levels among 82 patients; the figure legend gives 25 patients in each group. Patients with low BAP1 protein lived significantly longer than those with high BAP1 protein (31.9 months versus 17.1 months, p = 0.045). BAP1 mRNA levels were not prognostic in the TCGA and E-MTAB-1719 cohorts.
  • On tissue staining, tumors with low BAP1 had significantly more CD163-positive M2 macrophages. CD8-positive T cells did not differ significantly between the low- and high-BAP1 groups.
  • CD14-positive myeloid-derived suppressor cells were less abundant in low-BAP1 tumors than in high-BAP1 tumors. The text gives no p-value for this comparison.
  • In the Nanjing cohort, the authors reported that low-BAP1 tumors were enriched for precursor-exhausted CD8 T cells (positive for TCF1 and PD-1). The text gives no p-value; the figure panel prints P = 0.12.
  • In TCGA tumors, BAP1 inactivation was associated with significantly higher mRNA expression of the immune checkpoint receptors PD-L1 (CD274), PD-1 (PDCD1) and LAG3.
  • On multiplex staining, CD8 T cells were generally closer to mesothelin-positive tumor cells in low-BAP1 tumors than in high-BAP1 tumors.
  • In two data sets of immunotherapy-treated mice with mesothelioma, the main text reports that tumors responding to checkpoint inhibitors had significantly lower Bap1 levels than non-responding tumors. The Figure 4G caption states the opposite (higher Bap1 in responders), so the article contradicts itself on this result. The figure shows 12 versus 12 and 10 versus 10 tumors.
  • Tumor mutational burden did not differ significantly between BAP1-deficient and BAP1-proficient tumors.
  • Computer prediction estimated that BAP1-intact tumors were more sensitive to drugs targeting the MAPK-ERK pathway. In the Bern cohort, high-BAP1 tumors had higher levels of phosphorylated ERK1/2. In lab tests, a BAP1-proficient cell line was more sensitive to the MEK inhibitor trametinib.
• The authors' conclusion: The authors concluded that BAP1 deficiency defines an immune-inflamed type of malignant pleural mesothelioma that could be prioritized for checkpoint inhibitor treatment. They described BAP1 status as a candidate biomarker for immunotherapy response that warrants further clinical investigation.
• Limitations the authors state:
  • The analysis was retrospective, and the patient cohorts had not been treated with immune checkpoint inhibitors.
  • The findings on the immune environment rest largely on correlational analysis and need validation by independent experimental approaches.

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Biomarker, Immunotherapy, Pleural Mesothelioma, checkpoint inhibitors, Unresectable, Tumor Suppressor Gene, Molecular Profiling.

Related studies

• NF2 and Canonical Hippo-YAP Pathway Define Distinct Tumor Subsets Characterized by Different Immune Deficiency and Treatment Implications in Human Pleural Mesothelioma — H. Yang, S.R.R. Hall, et al. (2021)
• The role of PCMT1 in prognosis tumor immune microenvironment and therapeutic responses across cancers — B. Wang, S. Huang, et al. (2026)
• Loss of BAP1 as a candidate predictive biomarker for immunotherapy of mesothelioma — M. Ladanyi, F. Sanchez Vega, et al. (2019)
• Serum soluble mesothelin-related protein (SMRP) and fibulin-3 levels correlate with baseline malignant pleural mesothelioma (MPM) tumor volumes but are not useful as biomarkers of response in an immunotherapy trial — S.I. Katz, L. Roshkovan, et al. (2021)
• In-depth profiling of tumor tissue derived from malignant pleural mesothelioma patients identifies potential biomarkers predicting response to immune-checkpoint inhibitor therapy — D. Shek, B. Gao, et al. (2024)
• The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy — G.J. Chu, N. van Zandwijk, et al. (2019)

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