Thymoma Associated Myasthenia Gravis (TAMG): Differential Expression of Functional Pathways in Relation to MG Status in Different Thymoma Histotypes

Abstract

A unique feature of thymomas is their unrivaled frequency of associated myasthenia gravis (MG). Previous studies reported that MG+ thymomas contain a larger number of mature "pre-emigrant" CD4+ T cells than MG- thymomas and that most thymomas do not contain AIRE expressing cells irrespective of MG status. These findings suggest that CD4+ T cells that mature inside the abnormal microenvironment of thymomas and egress to the blood are critical to the development of thymoma-associated MG (TAMG) irrespective of thymoma histotype. However, underlying mechanisms have remained enigmatic. To get hints to mechanisms underlying TAMG, we pursue three hypotheses: (i) Functional pathways with metabolic and immunological relevance might be differentially expressed in TAMG(+) compared to TAMG(-) thymomas; (ii) differentially enriched pathways might be more evident in immature lymphocyte-poor (i.e., tumor cell/stroma-rich) thymoma subgroups; and (iii) mechanisms leading to TAMG might be different among thymoma histological subtypes. To test these hypotheses, we compared the expression of functional pathways with potential immunological relevance (N = 380) in relation to MG status separately in type AB and B2 thymomas and immature lymphocyte-rich and lymphocyte-poor subgroups of these thymoma types using the TCGA data set. We found that <10% of the investigated pathways were differentially upregulated or downregulated in MG+ compared to MG- thymomas with significant differences between AB and B2 thymomas. The differences were particularly evident, when epithelial cell/stroma-rich subsets of type AB and B2 thymomas were analyzed. Unexpectedly, some MG-associated pathways that were significantly upregulated in AB thymomas were significantly downregulated in B2 thymomas, as exemplified by the oxidative phosphorylation pathway. Conversely, the MG-associated pathway related to macrophage polarization was downregulated in MG+ AB thymoma and upregulated in MG+ B2 thymoma. We conclude that functional pathways are significantly associated with TAMG, and that some mechanisms leading to TAMG might be different among thymoma histological subtypes. Functions related to metabolisms, vascular and macrophage biology are promising new candidate mechanisms potentially involved in the pathogenesis of TAMG. More generally, the results imply that future studies addressing pathomechanisms of TAMG should take the histotype and abundance of tumor cells and non-neoplastic stromal components of thymomas into account.

Keywords: autoimmunity; functional pathways; macrophage polarization; metabolism; myasthenia gravis; the cancer genome atlas (TCGA); thymoma.