Overexpression and potential targeting of the oncofoetal antigen 5T4 in malignant pleural mesothelioma

Our plain-English summary of Overexpression and potential targeting of the oncofoetal antigen 5T4 in malignant pleural mesothelioma, by S. Al-Taei, J. Salimu, J.F. Lester, et al (Lung Cancer, 2012).

The study

• Authors: S. Al-Taei, J. Salimu, J.F. Lester, S. Linnane, M. Goonewardena, R. Harrop, M.D. Mason, Z. Tabi
• Journal: Lung Cancer
• Published: 2012;77(2):312-8
• Cited by: 29 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is resistant to conventional treatments. Novel, targeted treatments are hampered by the relative lack of MPM-associated tumour antigens. The aim of this study was to evaluate the level of expression and the relevance of 5T4 as a tumour-associated antigen in MPM. 5T4 expression was assessed by Western blotting, flow cytometry, immuno-cytochemistry and -histochemistry in 11 mesothelioma cell lines, 21 tumour biopsies, and ex vivo tumour cells obtained from the pleural fluid (PF) of 10 patients. 5T4 antibody levels were also determined in the plasma of patients and healthy donors. The susceptibility of MPM cells to 5T4-specific T-cell-mediated killing was determined using an HLA-A2(+), CD8(+) T-cell line, developed against the 5T4(17-25) peptide. We report here that cell surface 5T4 expression was detected in all mesothelioma cell lines and PF cell samples. Mesothelin and CD200, a suggested mesothelioma marker, were co-expressed with 5T4 on tumour cells in PF. Immunohistochemistry confirmed overexpression of 5T4, similar to mesothelin, on tumour cells but not on reactive stroma in all tissue sections tested. Median 5T4 antibody levels were 46% higher in patient than in healthy donor plasma, indicating immune recognition. Importantly, 5T4-specific CD8(+) T-cells were able to kill four out of six HLA-A2(+) MPM cell lines but not an HLA-A2(-) cell line, demonstrating immune recognition of MPM-associated 5T4 antigen at the effector T-cell level. We conclude that 5T4 is a potential new antigen for targeted therapies such as immunotherapy in MPM, as it is overexpressed on mesothelioma cells and recognised by 5T4-specific cytotoxic T-cells. Our findings have been translated into a Phase II clinical trial applying 5T4-targeted therapies in MPM patients.

Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

In plain English

This was a laboratory study from Cardiff, UK, of malignant pleural mesothelioma. It did not study asbestos exposure. The authors tested whether mesothelioma cells carry a protein called 5T4, a possible target for treatments such as vaccines. They examined 11 mesothelioma cell lines, tumour tissue, and tumour cells from the pleural fluid of 10 patients. All 11 cell lines, including one sarcomatoid line, carried 5T4. So did fluid cells from all 10 patients. In tumour tissue, 5T4 was seen on tumour cells, while normal pleura showed little staining. Median antibody levels against 5T4 were 46% higher in 17 patients than in 7 healthy donors, but the difference was not statistically significant (p = 0.472). The authors suggested the small number of samples as a likely reason. In a 5-hour laboratory test, immune cells trained against 5T4 killed four of six HLA-A2-positive cell lines (16–27% specific lysis, at 20 immune cells per tumour cell); the other two showed under 10%. The authors concluded that 5T4 is widely expressed in mesothelioma and can be a target for immune killing.

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 study of human mesothelioma cell lines, tumour tissue, pleural fluid cells and plasma (Western blotting, flow cytometry, immunocytochemistry, immunohistochemistry, antibody testing, and T-cell killing assays)
• Who was studied: Malignant pleural mesothelioma material from Cardiff, UK: 11 mesothelioma cell lines, 21 tumour biopsies, and pleural fluid tumour cells from 10 patients. Plasma came from 17 patients with malignant pleural mesothelioma and 7 healthy donors.
• Exposure: No asbestos or other exposure was studied. The study examined expression of the 5T4 protein and immune responses against it.
• Main results:
  • All 11 mesothelioma cell lines were positive for 5T4 by Western blot, including the sarcomatoid line M34. The LNCaP prostate cancer comparison cell line was negative.
  • Pleural fluid cells from all 10 patients expressed 5T4. In three patients, 73%, 83% and 83% of CD200-positive cells expressed 5T4.
  • Normal pleura showed little staining for 5T4 and mesothelin above the control. In tumour tissue, 5T4 staining was on tumour cells and not on reactive stroma or a blood vessel wall.
  • Median 5T4 antibody level was 46% higher in patient plasma (n = 17) than in healthy donor plasma (n = 7), but the difference was not statistically significant (p = 0.472).
  • 5T4-specific CD8+ T-cells killed four of six HLA-A2-positive mesothelioma cell lines. Killing measured 16–27% specific lysis at a 20:1 effector-to-target ratio in a 5-hour assay. This was significantly higher than for the HLA-A2-negative line M38.
  • Two of the six HLA-A2-positive lines (M15 and M40) showed less than 10% specific lysis. This resistance was not related to their level of 5T4 expression.
• The authors' conclusion: The authors concluded that 5T4 is widely expressed in mesothelioma tissues and cell lines and serves as a target for immune cell-mediated killing. They stated that these observations had been translated into a Phase II trial of the vaccine TroVax in patients with malignant pleural mesothelioma.
• Limitations the authors state:
  • The authors attributed the non-significant antibody difference probably to the small number of samples and one high healthy responder.
  • The authors stated that the significance of 5T4 antibody levels in malignant pleural mesothelioma is unknown.
  • The authors suggested that the 5-hour killing assay may not have been long enough to detect killing of the resistant cell lines.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelioma, Mesothelin, Immunohistochemistry, Immunotherapy, Clinical Trial.

Related studies

• A Tumor-Specific Neo-Antigen Caused by a Frameshift Mutation in BAP1 Is a Potential Personalized Biomarker in Malignant Peritoneal Mesothelioma — J. Lai, Z. Zhou, et al. (2016)
• Tumor-infiltrating dendritic cells exhibit defective cross-presentation of tumor antigens, but is reversed by chemotherapy — A.M. McDonnell, W.J. Lesterhuis, et al. (2015)
• Immunohistochemical Detection of Cancer-Testis Antigen PRAME — C. Lezcano, A.M. Müller, et al. (2021)
• Malignant mesothelioma-associated antigens recognized by tumor-infiltrating B cells and the clinical significance of the antibody titers — Y. Shigematsu, T. Hanagiri, et al. (2009)
• Evaluation of pleural CYFRA 21-1 and carcinoembryonic antigen in the diagnosis of malignant pleural effusions — G. Salama, M. Miédougé, et al. (1998)
• Distribution of the carbohydrate antigens, DU-PAN-2 and CA19-9, in tumors of the lung — G. Ohshio, K. Yamaki, et al. (1995)

Browse more research in Lung Cancer, or return to medical research.