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

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.

Cancer-Associated Fibroblasts Regulate Kinase Activity in Mesothelioma Cell Lines via Paracrine Signaling and Thereby Dictate Cell Faith and Behavior

“…A much stronger effect was observed after the usage of CM from IMR-90 in comparison to those from MRC-5. In a previous study, we were able to identify that cell–cell interaction via cytokines seems to be of greater importance in patients with an epithelioid subtype of MPM [ 27 ]. These results are consistent with our in vitro observation in this study since most of significant changes in phosphorylation pattern also occurred in the epithelioid NCI-H2052 cell line.…”

Cancer-Associated Fibroblasts Influence Survival in Pleural Mesothelioma: Digital Gene Expression Analysis and Supervised Machine Learning Model

“…Factorial normalization as well as biological normalization were performed with the geometric mean for all reference genes, as described in a previous study [50].…”

“…For statistical analysis, several tests were carried out prior to exploratory data analysis: Shapiro-Wilks test; Wilcoxon Mann-Whitney rank sum test or a two-sided Student's ttest; Kruskal-Wallis test or ANOVA; Fisher's exact test; Pearson's Chi-squared test and Spearman's rank correlation and Pearson's product-moment correlation were performed, as described elsewhere [50].…”

Malignant Mesothelioma

“…The involvement of the immune system is crucial in MM development and progression, however, as MM consists of different histological subtypes varying in aggressiveness, an important understanding of the biological background of its escape mechanisms was provided by Brcic, Mathilakathu et al [ 12 ]. With the development of immune checkpoint therapy, Kitajima et al also demonstrated how hybrid imaging modalities could contribute to therapy response assessment and predict prognosis [ 13 ].…”