Autoimmunity in thymic epithelial tumors: a not yet clarified pathologic paradigm associated with several unmet clinical needs

Abstract

Thymic epithelial tumors (TETs) are rare mediastinal cancers originating from the thymus, classified in two main histotypes: thymoma and thymic carcinoma (TC). TETs affect a primary lymphoid organ playing a critical role in keeping T-cell homeostasis and ensuring an adequate immunological tolerance against "self". In particular, thymomas and not TC are frequently associated with autoimmune diseases (ADs), with Myasthenia Gravis being the most common AD present in 30% of patients with thymoma. This comorbidity, in addition to negatively affecting the quality and duration of patients' life, reduces the spectrum of the available therapeutic options. Indeed, the presence of autoimmunity represents an exclusion criteria for the administration of the newest immunotherapeutic treatments with checkpoint inhibitors. The pathophysiological correlation between TETs and autoimmunity remains a mystery. Several studies have demonstrated the presence of a residual and active thymopoiesis in adult patients affected by thymomas, especially in mixed and lymphocytic-rich thymomas, currently known as type AB and B thymomas. The aim of this review is to provide the state of art in regard to the histological features of the different TET histotype, to the role of the different immune cells infiltrating tumor microenvironments and their impact in the break of central immunologic thymic tolerance in thymomas. We discuss here both cellular and molecular immunologic mechanisms inducing the onset of autoimmunity in TETs, limiting the portfolio of therapeutic strategies against TETs and greatly impacting the prognosis of associated autoimmune diseases.

Keywords: autoimmunity; immunotherapy; myasthenia gravis; surgery; thymic epithelial tumors; thymopoiesis.

Figure 1

Schematic representation of T cell development in normal thymus. Hematopoietic stem cells (HSC) deriving from the bone marrow seed the thymus and progress toward early thymocyte precursors (ETPs). ETPs moving within the cortex differentiate toward the double negative (DN) stage and before becoming double positive (DP) thymocytes, this DN-DP transition involves an immature single positive (ISP) intermediate characterized by the expression of the co-receptor CD4 and by the lack of CD3. Thymocytes interacting with major histocompatibility complex (MHC) molecules expressed by cortical thymus epithelial cells (cTECs) and dendritic cells (DCs) are positively selected. Thymocytes that do not recognize MHC molecules die for the loss of survival signals. Surviving thymocytes upregulate either CD4 or CD8 and migrate toward the medulla where negative selection, mediated by medullaryTECs (mTECs), DCs and a subset of B cells, induce the deletion of auto reactive thymocytes. A small fraction of thymocytes that show intermediate to high-affinity TCR that binds self-antigens and a high expression of CD25 escape clonal deletion becoming regulatory T cells (Treg). After completing the maturation CD4 or CD8 single-positive (SP) T cells leave the thymus, as recent thymic emigrants.