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

Carsten Sticht,Philipp Ströbel,Berthold Schalke,Julian Thelen,Alexander Marx,Yosuke Yamada,Cleo-Aron Weis

doi:10.3389/fimmu.2020.00664

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.

Highlights

Thymomas are tumors that appear to be derived from or show differentiation toward thymic epithelial cells, with a resemblance to the normal thymic histological architecture, such as discrete lobulation, perivascular spaces, and admixed immature T cells
According to the stratification of the thymoma cohorts described in Materials and Methods, the following myasthenia gravis (MG)+ and MGthymoma subgroups were compared in terms of gene expression followed by the extraction of functional pathways: [1] all type AB thymomas, [2] all type B2 thymomas, [3] TdT-low type AB thymomas, [4] TdT-high type AB thymomas, [5] TdT-low type B2 thymomas, and [6] TdT-high type B2 thymomas
Taking into account that inflammatory features of the thymoma microenvironment could be involve in the pathogenesis of thymoma-associated MG (TAMG), we focused on pathways (N = 70) that are related to inflammation, including features of tumor-infiltrating immune cells and cytokines [9]

Summary

Introduction

Thymomas are tumors that appear to be derived from or show differentiation toward thymic epithelial cells, with a resemblance to the normal thymic histological architecture, such as discrete lobulation, perivascular spaces, and admixed immature T cells. A recent comprehensive analysis of thymic epithelial tumors conducted as TCGA (The Cancer Genome Atlas) project has reported meaningful findings associated with TAMG, such as the higher prevalence of aneuploidy and overexpression of genes with sequence similarity with CHRNA1, TTN, and RYR1/RYR2 [8], all of which code for skeletal muscle antigens that are key autoantibody targets in TAMG, i.e., the α-subunit of the AChR, titin and ryanodine receptors, respectively [2] In spite of this progress, the underlying mechanisms leading to the above mentioned common features of MG-associated thymomas have remained largely enigmatic. Since the TCGA study did not reveal TAMGassociated “immune signatures” across the whole thymoma cohort [8], we here focused on histotype-specific enrichments of immunologically relevant pathways in association to TAMG

Methods

Results

Conclusion