CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness

Our plain-English summary of CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness, by S. Inaguma, J. Lasota, P. Czapiewski, et al (The Journal of Pathology, 2020).

The study

• Authors: S. Inaguma, J. Lasota, P. Czapiewski, R. Langfort, J. Rys, J. Szpor, P. Waloszczyk, K. Okoń, W. Biernat, D.S. Schrump, R. Hassan, K. Kasai, M. Miettinen, H. Ikeda
• Journal: The Journal of Pathology
• Published: 2020;250(2):205-216
• Cited by: 41 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Diffuse malignant mesothelioma of the pleura (MPM) is a highly aggressive tumour that typically is associated with short survival. CD70 and CD27 belong to the tumour necrosis factor (TNF) and the TNF receptor (TNFR) superfamily, respectively. Under physiological conditions, the tightly regulated interaction between CD70 and CD27 plays a co-stimulatory role in promoting T-cell expansion and differentiation through the NFκB pathway. Aberrantly high CD70 expression has been documented in haematological and solid malignancies in association with immune evasion in malignant cells. In this study, 172 well-characterised primary diffuse MPM tumours including epithelioid (n = 145), biphasic (n = 15), and sarcomatoid (n = 12) histotypes were evaluated immunohistochemically for CD70, CD27, CD3, CD4, CD8, CD56, PDCD1 (PD-1), and FOXP3 expression. Twenty per cent (34/172) of the mesothelioma cells expressed CD70 on the cell membrane. Overall survival was significantly decreased in the cohort of patients with CD70-expressing tumour cells (p < 0.01). Patients with MPM containing a higher number of CD3+ (p < 0.01), CD4+ (p < 0.01), CD8+ (p < 0.01), or FOXP3+ (p < 0.01) tumour-infiltrating lymphoid cells (TILs) showed significantly worse clinical outcomes. As potential independent risk factors for MPM patients, multivariate Cox proportional hazards regression analysis revealed CD70 expression on mesothelioma cells [hazard ratio (HR) 2.25; p = 0.010], higher FOXP3+ TILs (HR 2.81; p = 0.004), and higher CD3+ TIL accumulation (HR 6.12; p < 0.001). In contrast, as a potential independent favourable factor, higher CD27+ TIL accumulation (HR 0.48; p = 0.037) was identified. In vitro experiments and an immunodeficient mouse model revealed that CD70 enhances the invasiveness of MPM cells through MET-ERK axis activation. Further analyses in syngeneic mouse models demonstrated possible roles for CD70 in immune evasion. Collectively, these findings suggest that the CD70-CD27 pathway enhances the malignant phenotypes of MPM and diminishes anti-tumor immune response in patients with these neoplasms. These markers might be useful in MPM for prognostic evaluations as well as targeted therapeutics. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

© 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

In plain English

This laboratory study examined tumour samples from 172 people with diffuse malignant pleural mesothelioma (145 epithelioid, 15 biphasic, 12 sarcomatoid). The authors stained the samples for CD70, a protein found on some tumour cells, and counted several kinds of immune cells inside the tumours. CD70 appeared on the tumour cell membrane in 34 of 172 samples (20%). Survival was analysed in 63 patients. Median survival was 6.5 months when tumours showed membrane CD70, versus 18.0 months without it (p less than 0.01). In an analysis that took other factors into account, tumour CD70 had a hazard ratio of 2.25 (95% CI 1.21 to 4.17). Higher counts of FOXP3+ and CD3+ immune cells were also linked to worse survival, and higher counts of CD27+ immune cells to better survival. In cell and mouse experiments, mesothelioma cells made to produce CD70 migrated and invaded more and formed more aggressive tumours. The authors concluded that CD70 on pleural mesothelioma cells was associated with shorter survival. The authors called it a major limitation that asbestos exposure, smoking, tumour stage and treatment were not in the analysis.

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: Laboratory pathology study: immunohistochemical staining of human tumour samples with survival analysis (Kaplan–Meier and multivariate Cox regression), plus cell-culture experiments and mouse experiments
• Who was studied: 172 primary diffuse malignant pleural mesothelioma tumours (145 epithelioid, 15 biphasic, 12 sarcomatoid). 30 came from patients on IRB-approved protocols at the US National Institutes of Health, and 142 were additional anonymised samples. Survival was analysed for 63 patients, followed up for up to 120 months. Collection dates and countries for the anonymised samples are not stated. The study also used human and mouse mesothelioma cell lines and immunodeficient (NOD/SCID) and BALB/c mice.
• Exposure: No asbestos or other environmental exposure was studied. The factors examined were CD70 on tumour cells (positive at 5% or more of cells) and counts of immune cells in the tumour stained for CD27, CD3, CD4, CD8, CD56, PDCD1 (PD-1) and FOXP3. Asbestos exposure data were not included in the analysis.
• Main results:
  • CD70 was expressed on the tumour cell membrane in 34 of 172 mesothelioma samples (20%).
  • Among the 63 patients analysed for survival, median survival was 6.5 months with membrane CD70 on tumour cells versus 18.0 months without CD70 expression or with cytoplasmic labelling only (p < 0.01).
  • In the multivariate Cox analysis, CD70 expression on mesothelioma cells was a potential independent risk factor: hazard ratio 2.25 (95% CI 1.21–4.17; p = 0.010).
  • In the multivariate analysis, higher FOXP3+ tumour-infiltrating lymphocytes (19 or more per high-power field) were a potential independent risk factor: HR 2.81 (95% CI 1.39–5.66; p = 0.0040).
  • In the multivariate analysis, higher CD3+ tumour-infiltrating lymphocytes (3 or more per high-power field) were a potential independent risk factor: HR 6.12 (95% CI 2.64–14.2; p < 0.001).
  • In the multivariate analysis, higher CD27+ tumour-infiltrating lymphocytes (15 or more per high-power field) were a potential independent favourable factor: HR 0.48 (95% CI 0.25–0.96; p = 0.037).
  • In the survival analysis that did not adjust for other factors, higher numbers of CD3+, CD4+, CD8+ and FOXP3+ tumour-infiltrating lymphocytes were each significantly associated with worse survival (p < 0.01 each).
  • CD70-positive tumours contained significantly more FOXP3+ tumour-infiltrating lymphocytes than CD70-negative tumours (p = 0.0024).
  • In cell experiments, forcing CD70 expression increased migration and invasion of MeT-5A mesothelial cells and H2052 mesothelioma cells. The authors attributed this to activation of MET–ERK signalling.
  • In the first syngeneic mouse experiment, five of six mice given CD70-expressing AB1 cells in the chest died of tumour on days 10–11. No lesions were found in control mice examined on day 25.
  • In the second syngeneic mouse experiment, tumour diameter did not differ significantly between groups. Tumours from CD70-expressing cells contained significantly more FOXP3+, PDCD1+ and HAVCR2 (TIM-3)+ immune cells.
• The authors' conclusion: The authors concluded that CD70 expression on pleural mesothelioma cells was associated with shorter survival. They stated that their molecular and animal studies showed CD70 worsened prognosis through enhanced invasiveness and immune evasion. They suggested CD70 and the other markers could be useful for prognosis and treatment planning.
• Limitations the authors state:
  • The survival model did not include asbestos exposure, smoking, tumour stage or treatment, because clinical information was limited and many samples were small biopsies not useful for staging. The authors called this a major limitation.
  • It remains unclear whether CD70 directly interacts with MET to stabilise it.

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: Prognosis, Pleural Mesothelioma, Malignant Mesothelioma, Pleura, Necrosis, Epithelioid, Biphasic Mesothelioma, Sarcomatoid.

Related studies

• Expression of ALCAM (CD166) and PD-L1 (CD274) independently predicts shorter survival in malignant pleural mesothelioma — S. Inaguma, J. Lasota, et al. (2018)
• Tumoral CD10 expression correlates with aggressive histology and prognosis in patients with malignant pleural mesothelioma — K. Kadota, J. Villena-Vargas, et al. (2015)
• Immune biomarkers PD-1/PD-L1 and TLR3 in malignant pleural mesotheliomas — C. Combaz-Lair, F. Galateau-Sallé, et al. (2016)
• Characterization of soluble PD-L1 in pleural effusions of mesothelioma patients: potential implications in the immune response and prognosis — R. Carosio, V. Fontana, et al. (2021)
• Sustained expression of steroid receptor coactivator SRC-2/TIF-2 is associated with better prognosis in malignant pleural mesothelioma — C.J. Jennings, A. O'Grady, et al. (2012)
• High BIN1 expression has a favorable prognosis in malignant pleural mesothelioma and is associated with tumor infiltrating lymphocytes — T. Ahmadzada, K. Lee, et al. (2019)

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