CD70 and PD-L1 (CD274) co-expression predicts poor clinical outcomes in patients with pleural mesothelioma

Our plain-English summary of CD70 and PD-L1 (CD274) co-expression predicts poor clinical outcomes in patients with pleural mesothelioma, by S. Inaguma, A. Ueki, J. Lasota, et al (The Journal of Pathology. Clinical Research, 2023).

The study

• Authors: S. Inaguma, A. Ueki, J. Lasota, M. Komura, A.N. Sheema, P. Czapiewski, R. Langfort, J. Rys, J. Szpor, P. Waloszczyk, K. Okoń, W. Biernat, D.S. Schrump, R. Hassan, M. Miettinen, S. Takahashi
• Journal: The Journal of Pathology. Clinical Research
• Published: 2023;9(3):195-207
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Diffuse pleural mesothelioma (PM) is a highly aggressive tumour typically associated with short survival. Recently, the effectiveness of first-line immune checkpoint inhibitors in patients with unresectable PM was reported. CD70-CD27 signalling plays a co-stimulatory role in promoting T cell expansion and differentiation through the nuclear factor κB (NF-κB) pathway. Conversely, the PD-L1 (CD274)-PD-1 (PDCD1) pathway is crucial for the modulation of immune responses in normal conditions. Nevertheless, pathological activation of both the CD70-CD27 and PD-L1-PD-1 pathways by aberrantly expressed CD70 and PD-L1 participates in the immune evasion of tumour cells. In this study, 171 well-characterised PMs including epithelioid (n = 144), biphasic (n = 15), and sarcomatoid (n = 12) histotypes were evaluated immunohistochemically for CD70, PD-L1, and immune cell markers such as CD3, CD4, CD8, CD56, PD-1, FOXP3, CD68, and CD163. Eight percent (14/171) of mesotheliomas simultaneously expressed CD70 and PD-L1 on the tumour cell membrane. PMs co-expressing CD70 and PD-L1 contained significantly higher numbers of CD8+ (p = 0.0016), FOXP3+ (p = 0.00075), and CD163+ (p = 0.0011) immune cells within their microenvironments. Overall survival was significantly decreased in the cohort of patients with PM co-expressing CD70 and PD-L1 (p < 0.0001). In vitro experiments revealed that PD-L1 and CD70 additively enhanced the motility and invasiveness of PM cells. In contrast, PM cell proliferation was suppressed by PD-L1. PD-L1 enhanced mesenchymal phenotypes such as N-cadherin up-regulation. Collectively, these findings suggest that CD70 and PD-L1 both enhance the malignant phenotypes of PM and diminish anti-tumour immune responses. Based on our observations, combination therapy targeting these signalling pathways might be useful in patients with PM.

© 2023 The Authors. The Journal of Pathology: Clinical Research published by The Pathological Society of Great Britain and Ireland and John Wiley & Sons Ltd.

In plain English

This laboratory study examined tumour samples from 171 patients with diffuse pleural mesothelioma (144 epithelioid, 15 biphasic, 12 sarcomatoid): 30 from the US National Institutes of Health and 141 from institutions in Poland. The authors stained the samples for two tumour-cell proteins, CD70 and PD-L1, and counted immune cells. Some of this staining data came from the group's earlier reports. CD70 was found in 34 (20%) of the 171 tumours, PD-L1 in 54 (32%), and both in 14 (8%). Tumours with both proteins contained more CD8+, FOXP3+ and CD163+ immune cells. Among 63 patients analysed for survival, those whose tumours carried both proteins had significantly shorter survival (1.5 months; 95% CI 0 to 11.5). Compared with all other patients, the hazard ratio for having both proteins was 9.35 (95% CI 3.02 to 28.94). In cell-line experiments, adding CD70 and PD-L1 increased cell migration and invasion. The authors concluded that expression of both proteins was associated with shorter survival. They listed as limitations the small number of patients and the lack of asbestos exposure histories.

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: Pathology study of archived tumour samples (immunohistochemistry on multi-tumour tissue blocks) with survival analysis (log-rank tests and Cox regression), combined with in vitro experiments on mesothelial and mesothelioma cell lines. The CD70, PD-L1, PD-1 and FOXP3 staining data were cited from the group's previous reports.
• Who was studied: 171 diffuse pleural mesotheliomas: 30 from patients on National Institutes of Health protocols and 141 anonymised samples from multiple institutions in Poland. By histotype, 144 were epithelioid, 15 biphasic and 12 sarcomatoid. 63 patients were analysed for survival, with follow-up of up to 120 months. Study dates are not given. Cell lines used: MeT-5A (immortalised mesothelial) and six mesothelioma lines.
• Exposure: Asbestos exposure was not studied. The factors examined were membrane expression of the proteins CD70 and PD-L1 on tumour cells (positive at a 5% cut-off) and counts of immune cells in the tumour (CD3, CD4, CD8, CD56, PD-1, FOXP3, CD68, CD163). In the cell experiments, PD-L1 was depleted, or CD70 and/or PD-L1 were added to cells.
• Main results:
  • Of the 171 tumours, 34 (20%) expressed CD70, 54 (32%) expressed PD-L1, and 14 (8%) expressed both.
  • Tumours expressing both CD70 and PD-L1 contained significantly higher numbers of CD8+ (p = 0.0016), FOXP3+ (p = 0.00075) and CD163+ (p = 0.0011) immune cells.
  • Among the 63 patients analysed for survival, survival was significantly shorter in patients whose tumours expressed both CD70 and PD-L1: 1.5 months (95% CI 0 to 11.5; p less than 0.0001).
  • In multivariate Cox analysis, tumours positive for both proteins (versus all others) had a hazard ratio of 9.35 (95% CI 3.02 to 28.94; p less than 0.001). Higher FOXP3+ cell counts (HR 2.27; 95% CI 1.05 to 4.91) and CD3+ cell counts (HR 7.80; 95% CI 3.20 to 19.04) were also identified as potential independent risk factors.
  • Higher PD-1+ cell counts (HR 0.41; 95% CI 0.20 to 0.86) and CD56+ cell counts (HR 0.45; 95% CI 0.24 to 0.82) were identified as potential independent favourable factors.
  • In two cell lines (MeT-5A and H2052), reducing PD-L1 increased cell proliferation and suppressed cell migration.
  • In two mesothelioma cell lines (Y-MESO-8A and ACC-MESO-4), adding CD70 and PD-L1 increased migration and invasion, and the two effects were additive. PD-L1 slightly suppressed proliferation.
  • Cells given PD-L1 showed up-regulation of N-cadherin and/or VIM, markers of a mesenchymal phenotype.
• The authors' conclusion: The authors concluded that expression of both CD70 and PD-L1 on tumour cells was associated with shorter survival in pleural mesothelioma. In their view, the two proteins worsened prognosis by enhancing invasiveness and immune evasion, and combination therapies targeting the CD70–CD27 and PD-L1–PD-1 pathways might be useful.
• Limitations the authors state:
  • The number of patients was small, and clinical information was lacking, including history of asbestos exposure, smoking and treatment.
  • Tumour staging was difficult because many samples were small biopsy specimens.
  • Variation within tumours and in marker staining must be considered when tissue arrays contain small specimens.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: PD-L1, Pleural Mesothelioma, checkpoint inhibitors, Unresectable, Epithelioid, Biphasic Mesothelioma, Sarcomatoid, Mesothelioma.

Related studies

• CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness — S. Inaguma, J. Lasota, et al. (2020)
• Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma — S. Inaguma, J. Lasota, et al. (2018)
• CD157 enhances malignant pleural mesothelioma aggressiveness and predicts poor clinical outcome — E. Ortolan, A. Giacomino, et al. (2014)
• Comprehensive immunohistochemical study of mesothelin (MSLN) using different monoclonal antibodies 5B2 and MN-1 in 1562 tumors with evaluation of its prognostic value in malignant pleural mesothelioma — S. Inaguma, Z. Wang, et al. (2017)
• The phenogenomic landscapes of pleural mesothelioma tumor microenvironment predict clinical outcomes — F. Torricelli, F. Spada, et al. (2025)
• B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis — A.S. Mansfield, A.C. Roden, et al. (2014)

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