BAP1 Loss in Pleural Mesothelioma Is Associated With Reduced Soluble CCL2 in Patient Effusion, Abrogated CCL2-Mediated Monocyte Recruitment In Vitro

Our plain-English summary of BAP1 Loss in Pleural Mesothelioma Is Associated With Reduced Soluble CCL2 in Patient Effusion, Abrogated CCL2-Mediated Monocyte Recruitment In Vitro, by A. Nash, E. Rouse, T. Firth, et al (JTO Clinical and Research Reports, 2026).

The study

• Authors: A. Nash, E. Rouse, T. Firth, I.M. Dick, V.S. Fear, C.A. Forbes, A. Louw, Y.C.G. Lee, A.J. Redwood, B.W. Robinson, J. Creaney
• Journal: JTO Clinical and Research Reports
• Published: 2026;7(10):101049
• Read it: PubMed · Publisher · Free full text

Abstract

Objectives: Pleural mesothelioma is an incurable cancer of the cell layer lining the chest wall and lung. Patients frequently present with pleural effusion, which is often drained for symptom relief and enables minimally invasive sampling of the tumour environment, including immune cells and related soluble factors. Most of the mesothelioma tumours exhibit loss of BRCA1-associated protein 1 (BAP1), a multifunctional tumour suppressor protein. Here, we aim to elucidate the effect of BAP1 loss on the mesothelioma microenvironment through profiling soluble factors within pleural effusion.

Methods: A custom panel of 22 soluble factors was measured by Luminex assay and enzyme-linked immunosorbent assay in an initial cohort of 40 patients with known BAP1 status. Validation was performed by enzyme-linked immunosorbent assay in an independent cohort of 100 cases. Secretion of soluble factors and chemoattraction of monocytes were characterised using a CRISPR-mediated BAP1 deletion model in a mesothelioma and a lung cancer cell line. Immune cell infiltration, estimated by CIBERSORT, was further explored in the Cancer Genome Atlas -MESO cohort.

Results: Soluble C-C motif chemokine ligand 2 (CCL2) was approximately 55% to 60% lower in pleural effusion from BAP1-loss cases in both independent cohorts. Deletion of BAP1 reduced CCL2 secretion in vitro and abolished CCL2-mediated chemoattraction of monocytes in both mesothelioma and lung cancer cell lines. In the Cancer Genome Atlas -MESO cohort, BAP1-mutant tumours exhibited a reduction in estimated macrophage content.

Conclusion: Loss of BAP1 impairs CCL2 secretion into pleural effusions, potentially influencing monocyte recruitment into the tumour microenvironment.

© 2026 The Authors.

In plain English

This laboratory and clinical-sample study examined whether tumour BAP1 status relates to soluble factors in pleural effusions from patients with pleural mesothelioma, described in the introduction as an asbestos-related cancer. In a discovery cohort of 40 effusions (20 with BAP1 loss, 20 with BAP1 retention), 22 soluble factors were measured by Luminex assay and ELISA; CCL2 best distinguished BAP1 status (AUC = 0.70), with lower levels in BAP1-loss cases. By ELISA, CCL2 was higher with BAP1 retention in the discovery cohort (p = 0.030) and in an independent validation cohort of 100 effusions (2864 [1133-4944] versus 1163 [612-2421] pg/mL, p = 0.0025). CRISPR deletion of BAP1 lowered CCL2 secretion in JU77 mesothelioma and A549 lung cancer cells, and reduced monocyte migration toward JU77 supernatant. An anti-CCL2 antibody reduced migration toward JU77 BAP1 wild-type supernatant. In TCGA-MESO (n = 74), estimated total macrophage content was higher in BAP1 wild-type than BAP1-mutant tumours (p = 0.034). The authors concluded that BAP1 loss impairs CCL2 secretion into effusions, potentially influencing monocyte recruitment.

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: Analysis of banked patient pleural effusion samples (discovery and validation cohorts) combined with in vitro CRISPR BAP1-deletion cell-line experiments and secondary analysis of public TCGA-MESO data
• Who was studied: Patients with pleural mesothelioma: a discovery cohort of 40 (20 BAP1 retained, 20 BAP1 loss) and a validation cohort of 100 (45 BAP1 retained, 55 BAP1 loss)
• Exposure: Not an exposure study: the variable examined was tumour BAP1 protein status (loss versus retention by immunohistochemistry, or BAP1 mutation in TCGA, or CRISPR knockout in cell lines); asbestos is mentioned only as the cause of mesothelioma
• Main results:
  • In the discovery cohort, CCL2 was the single most predictive factor of BAP1 status among the 22 markers, with lower concentrations in BAP1 loss
  • Discovery cohort, CCL2 by ELISA: higher in BAP1-retained than BAP1-loss effusions (medians 1232 versus 670 pg/mL, p = 0.030); the printed interquartile ranges appear transposed
  • Validation cohort of 100 effusions: CCL2 higher in BAP1-retained than BAP1-loss group
  • Serum: no correlation with effusion CCL2 and no significant difference by BAP1 status in the 22 matched samples
  • Validation cohort survival: BAP1 retention was associated with shorter survival (median 10.8 versus 22.2 months)
  • Validation cohort multivariate analysis: BAP1 retention (hazard ratio 1.84), non-epithelioid histology (2.85) and poor performance status (3.26) were associated with shorter survival
  • Effusion CCL2 was not significantly associated with survival in either cohort after correction for clinical characteristics
  • In vitro, CRISPR BAP1 knockout clones secreted less CCL2 than BAP1 wild-type clones in both cell lines
  • Monocyte migration toward JU77 supernatant was significantly reduced with BAP1 knockout
  • For A549, monocyte migration was higher with BAP1 wild-type supernatant but the difference was not statistically significant
  • CCL2-neutralising antibody reduced monocyte migration toward JU77 BAP1 wild-type supernatant
  • TCGA-MESO (n = 74): estimated total macrophage content higher in BAP1 wild-type than BAP1-mutant tumours; CCL2 mRNA not significantly altered
  • HMGB1 did not differ significantly between BAP1 subgroups, and no other panel cytokine was significantly associated with BAP1 status
• The authors' conclusion: The authors concluded that BAP1 loss reduces CCL2 in pleural effusion and may thereby reduce recruitment of monocyte-derived macrophages, supporting a rationale for targeting the CCL2-CCR2 axis in BAP1-retained patients
• Limitations the authors state:
  • No paired tumour tissue and effusion samples, so effusion CCL2 could not be related to tumour monocyte or macrophage infiltration
  • The cohort was enriched for epithelioid histology, and BAP1 loss is more frequent in epithelioid disease
  • BAP1 retention on immunohistochemistry does not necessarily mean the protein is functional

Topics

Medical terms in this study, explained in our Lexicon: BAP1, Pleural Mesothelioma, Pleural Effusion, Mesothelioma, Lung Cancer, Macrophage.

Related studies

• Pleural Effusions from Patients with Mesothelioma Induce Recruitment of Monocytes and Their Differentiation into M2 Macrophages — A.L. Chéné, S. d'Almeida, et al. (2016)
• Profile of soluble factors in pleural effusions predict prognosis in mesothelioma — I.M. Dick, Y.C.G. Lee, et al. (2022)
• SIRT3 Overexpression Ameliorates Asbestos-Induced Pulmonary Fibrosis, mt-DNA Damage, and Lung Fibrogenic Monocyte Recruitment — P. Cheresh, S.J. Kim, et al. (2021)
• The Sphingosine Kinase 1 Inhibitor, PF543, Mitigates Pulmonary Fibrosis by Reducing Lung Epithelial Cell mtDNA Damage and Recruitment of Fibrogenic Monocytes — P. Cheresh, S.J. Kim, et al. (2020)
• Inhibition of the Histone Methyltransferase EZH2 Enhances Protumor Monocyte Recruitment in Human Mesothelioma Spheroids — S. Mola, G. Pinton, et al. (2021)
• Pathogenesis of mesothelial reactions to asbestos fibers. Monocyte recruitment and macrophage activation — R.M. Branchaud, L.J. Garant, et al. (1993)

Browse more research in JTO Clinical and Research Reports, or return to medical research.