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

Duo Xu, MD, PhD; Yanyun Gao, PhD; Haitang Yang, MD, PhD; Marc Spils, MD; Thomas M. Marti, PhD; Tereza Losmanová, MD; Min Su, PhD; Wenxiang Wang, MD; Qinghua Zhou, MD; Patrick Dorn, MD; Yongqian Shu, MD, PhD; Ren-Wang Peng, PhD

JTO Clinical and Research Reports (May 2024)

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

Duo Xu, MD, PhD,
Yanyun Gao, PhD,
Haitang Yang, MD, PhD,
Marc Spils, MD,
Thomas M. Marti, PhD,
Tereza Losmanová, MD,
Min Su, PhD,
Wenxiang Wang, MD,
Qinghua Zhou, MD,
Patrick Dorn, MD,
Yongqian Shu, MD, PhD,
Ren-Wang Peng, PhD

Affiliations

Duo Xu, MD, PhD: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
Yanyun Gao, PhD: Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland
Haitang Yang, MD, PhD: Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
Marc Spils, MD: Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland
Thomas M. Marti, PhD: Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland
Tereza Losmanová, MD: Institute of Tissue Medicine and Pathology, University of Bern, Bern, Switzerland
Min Su, PhD: The Second Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China
Wenxiang Wang, MD: The Second Department of Thoracic Surgery, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, People’s Republic of China
Qinghua Zhou, MD: Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, People’s Republic of China
Patrick Dorn, MD: Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland
Yongqian Shu, MD, PhD: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China
Ren-Wang Peng, PhD: Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland; Department for BioMedical Research, University of Bern, Bern, Switzerland; Corresponding author. Address for correspondence: Ren-Wang Peng, PhD, Department of General Thoracic Surgery and Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, Murtenstrasse 28, CH-3008 Bern, Switzerland.

Journal volume & issue: Vol. 5, no. 5
p. 100672

Abstract

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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.

Published in JTO Clinical and Research Reports

ISSN: 2666-3643 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.journals.elsevier.com/jto-clinical-and-research-reports/

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