Digital Gene Expression Analysis of Epithelioid and Sarcomatoid Mesothelioma Reveals Differences in Immunogenicity

Our plain-English summary of Digital Gene Expression Analysis of Epithelioid and Sarcomatoid Mesothelioma Reveals Differences in Immunogenicity, by L. Brcic, A. Mathilakathu, R.F.H. Walter, et al (Cancers, 2021).

The study

• Authors: L. Brcic, A. Mathilakathu, R.F.H. Walter, M. Wessolly, E. Mairinger, H. Beckert, D. Kreidt, J. Steinborn, T. Hager, D.C. Christoph, J. Kollmeier, T. Mairinger, J. Wohlschlaeger, K.W. Schmid, S. Borchert, F.D. Mairinger
• Journal: Cancers
• Published: 2021;13(8)
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignancy associated with asbestos exposure. Median survival ranges from 14 to 20 months after initial diagnosis. As of November 2020, the FDA approved a combination of immune checkpoint inhibitors after promising intermediate results. Nonetheless, responses remain unsatisfying. Adequate patient stratification to improve response rates is still lacking. This retrospective study analyzed formalin fixed paraffin embedded specimens from a cohort of 22 MPM. Twelve of those samples showed sarcomatoid, ten epithelioid differentiation. Complete follow-up, including radiological assessment of response by modRECIST and time to death, was available with reported deaths of all patients. RNA of all samples was isolated and subjected to digital gene expression pattern analysis. Our study revealed a notable difference between epithelioid and sarcomatoid mesothelioma, showing differential gene expression for 304/698 expressed genes. Whereas antigen processing and presentation to resident cytotoxic T cells as well as phagocytosis is highly affected in sarcomatoid mesothelioma, cell-cell interaction via cytokines seems to be of greater importance in epithelioid cases. Our work reveals the specific role of the immune system within the different histologic subtypes of MPM, providing a more detailed background of their immunogenic potential. This is of great interest regarding therapeutic strategies including immunotherapy in mesothelioma.

In plain English

This laboratory study examined tumor tissue samples taken before treatment and preserved in paraffin. The samples came from 22 patients with malignant pleural mesothelioma treated in Essen and Berlin, Germany, between 2002 and 2009. Twelve tumors were sarcomatoid and 10 were epithelioid. The authors measured immune-related gene activity using a commercial panel of 770 such genes. The article did not report the patients' asbestos exposure. Of 698 genes found to be active, 304 (43.6%) differed between the two subtypes: 214 were more active in epithelioid tumors and 90 in sarcomatoid tumors. Sarcomatoid tumors showed enrichment of genes linked to phagocytosis (engulfing material) and to processing and presenting antigens to immune cells. Epithelioid tumors showed enrichment of cytokine signaling genes, which the authors called potentially activated. The gene-expression analysis did not detect a difference in estimated CD8+ cytotoxic T-cell infiltration between subtypes. The authors concluded that this knowledge could help select patients for treatments such as immune checkpoint blockade. They noted that the study rested on gene expression data only and that the sample sizes were small.

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: Retrospective laboratory study comparing gene expression in stored tumor tissue from two mesothelioma subtypes
• Who was studied: Tumor samples taken before treatment from 22 patients with malignant pleural mesothelioma: 12 sarcomatoid (SMM) and 10 epithelioid (EMM). Patients were treated at the West German Cancer Centre or West German Lung Centre (Essen, 2006 to 2009) and Helios Klinikum Emil von Behring (Berlin, 2002 to 2009). All received platinum-based chemotherapy, and all had died by the end of follow-up on August 31, 2014.
• Exposure: No asbestos exposure was measured or reported for these patients. The study compared the activity of immune-related genes (NanoString panel of 770 immune-related genes plus 30 reference genes) between epithelioid and sarcomatoid tumors.
• Main results:
  • Of 698 expressed immune-related genes, 304 (43.6%) differed in expression between epithelioid and sarcomatoid tumors.
  • Of the 304 differing genes, 90 (29.6%) were expressed only or much more strongly in sarcomatoid tumors, and 214 (70.4%) were overexpressed in epithelioid tumors.
  • ABCB1, SYCP1 and IFNA7 were expressed in epithelioid tumors but absent in sarcomatoid tumors. MAPK8, AXL and UBC were expressed mainly in sarcomatoid tumors.
  • Based on gene expression, no difference in estimated CD8+ cytotoxic T-cell infiltration was detected between the subtypes (FDR adjusted p = 0.901).
  • CD4+ T cells and CD68+ macrophages were enriched in sarcomatoid tumors.
  • CD20+ B cells tended to be denser in epithelioid tumors, but this was not statistically significant after adjustment (p = 0.050; FDR adjusted p = 0.094).
  • In sarcomatoid tumors, the gene sets showing the strongest enrichment included phagosome, antigen processing and presentation, and lysosome, among others.
  • In epithelioid tumors, cytokine to cytokine receptor interaction genes were enriched. The authors described this pathway as potentially activated.
  • Chemokines binding CXCR1 and CXCR2 were expressed in epithelioid tumors. Those binding CXCR3 or CXCR5 were expressed in sarcomatoid tumors.
• The authors' conclusion: The authors concluded that epithelioid and sarcomatoid mesothelioma show distinct patterns of immune-related gene activity. In their view, knowledge of these processes has the potential to support patient stratification for treatments such as immune checkpoint blockade.
• Limitations the authors state:
  • The study was based only on gene expression data, so direct proof of differences in the immune cells present and in chemokine secretion is lacking.
  • The sample sizes of both subtypes were relatively small, which reduces study strength.
  • There was no comparison with normal mesothelium, because normal pleural tissue from healthy patients is rarely available.

Topics

Medical terms in this study, explained in our Lexicon: Epithelioid, Sarcomatoid, Mesothelioma, Pleural Mesothelioma, Asbestos Exposure, Median Survival, checkpoint inhibitors, Phagocytosis.

Related studies

• Mitogen signal-associated pathways, energy metabolism regulation, and mediation of tumor immunogenicity play essential roles in the cellular response of malignant pleural mesotheliomas to platinum-based treatment: a retrospective study — A. Mathilakathu, S. Borchert, et al. (2021)
• Screening of Pleural Mesotheliomas for DNA-damage Repair Players by Digital Gene Expression Analysis Can Enhance Clinical Management of Patients Receiving Platin-Based Chemotherapy — R.F. Walter, C. Vollbrecht, et al. (2016)
• One Third of Malignant Pleural Mesothelioma Shows High Immunohistochemical Expression of MSLN or CXCR4 Which Indicates Potent Candidates for Endo-Radiotherapy — T. Hager, S. Borchert, et al. (2023)
• Expression Profiles of Cytokine mRNAs in the Pleural Fluid Reveal Differences Among Tuberculosis, Malignancies, and Pneumonia-Exudative Pleural Effusions — D.L. Espósito, V.R. Bollela, et al. (2015)
• Mdm2 protein expression is strongly associated with survival in malignant pleural mesothelioma — F.D. Mairinger, R.F. Walter, et al. (2014)
• Gene expression profiles reveal increased mClca3 (Gob5) expression and mucin production in a murine model of asbestos-induced fibrogenesis — T. Sabo-Attwood, M. Ramos-Nino, et al. (2005)

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