Unraveling the Immune Microenvironment of Thymic Epithelial Tumors: Implications for Autoimmunity and Treatment

Abstract

Thymic Epithelial Tumors (TETs) represent a rare tumor family, originating from the epithelial component of the thymus gland. Clinicopathologically, they are segregated into six major subtypes, associated with distinct histological features and clinical outcomes. Their emergence and evolution are accompanied by the generation of a complex tumor microenvironment (TME), dominated by phenotypically and functionally divergent immune cellular subsets, in different maturation states and in analogies that vary significantly among different subtypes. These heterogenous leukocyte populations exert either immune-permissive and tumor-suppressive functions or vice versa, and the dynamic equilibrium established among them either dictates the tumor immune milieu towards an immune-tolerance state or enables the development of a productive spontaneous tumoricidal response. The immunologically “hot” microenvironment, defining a significant proportion of TETs, makes them a promising candidate for the implementation of immune checkpoint inhibitors (ICIs). A number of phase I and II clinical trials have already demonstrated significant, type-specific clinical efficacy of PD-L1 inhibitors, even though substantial limitations in their utilization derive from their immune-mediated adverse effects. Moreover, the completed clinical studies involved relatively restricted patient samples and an expansion in the enrolled cohorts is required, so that more trustworthy conclusions regarding the benefit from ICIs in TETs can be extracted.

Tumor Microenvironment in Thymic Epithelial Tumors: A Narrative Review

“…PD-L1 binds to the PD-1 receptor, which is expressed on the surface of T cells, and plays an important role in immune response modulation through the suppression of cytokine production, T-cell proliferation, and T-cell adhesion [ 11 , 22 , 23 , 24 , 25 , 26 ]. In general, the TME of subtypes A, AB, B1, and B2 thymomas is infiltrated mainly by immature T-cells (CD4+ CD8+), which means that their immune status simulates the normal thymocytes [ 27 ]. In the case of advanced WHO histological types (B3 thymomas and thymic carcinomas), there are fully differentiated cytotoxic T-cells.…”

“…As already mentioned, the immune cells can have a favorable effect in tumor genesis and progression, while others can have anti-tumoral functions. This dynamic state and equilibrium in the TME could, however, twist the balance to one or the other side, resulting, therefore, in tumor evolution or suppression [ 27 ]. From all the above, it is obvious that the TME of TET represents a wide field, where more research is warranted in order to draw pertinent conclusions concerning the predictive role of each element that is described.…”

Thymic Epithelial Tumors: An Evolving Field

“…The TET microenvironment overlaps largely with the normal thymus components. Predictably, thymomas show a higher proportion of lymphocytic infiltrate compared to thymic carcinomas; AB, B1, and B2 thymomas show a higher proportion of CD4+/CD8+ immature cells, while B3 thymomas and thymic carcinomas show numerous terminally differentiated CD4+ or CD8+ cells, mostly polarized toward a CD8+ cytotoxic phenotype [ 93 ]. Thymic carcinomas also show a lower expression of the pro-inflammatory gene HMGB1, portending a less favorable prognosis [ 94 , 95 ].…”

“…B-cells are particularly enriched in certain TET subtypes (micronodular thymoma or carcinoma with lymphoid hyperplasia) and in MG-associated TETs and other autoimmune disorders [ 93 , 96 ]. Lower-grade TETs, such as B1 and B2 thymomas, also show higher percentages of fascin and S100 positive dendritic cells compared to thymic carcinomas [ 97 , 98 ].…”

Emerging therapies in thymic epithelial tumors (Review)

“…Current research perspective in TETs involves the genomic characterization of the tumors, the exploration of oncogenic pathways and the investigation of the tumor microenvironment, especially regarding its unique tissue-specific immune component ( 6 , 7 ). Alternative therapeutic options are emerging, including targeted agents and immune checkpoint inhibitors ( Fig.…”