Immune-related markers define clinically relevant prognostic subgroups in thymic epithelial tumors

BACKGROUND: Characterizing the immune landscape of thymic epithelial tumors (TETs) is essential for patient stratification for emerging immunotherapeutic approaches and for optimizing follow-up strategies. In this study, we examined the expression patterns and clinical significance of five immune-related markers in a large cohort of TETs. MATERIAL AND METHODS: Expression of TIM3, OX40L, GTF2I, XPO1, and GITR was assessed by immunohistochemistry (IHC) in the epithelial and lymphocytic compartments of 137 surgically resected TETs and correlated with clinicopathological parameters and patient outcomes. Tumors were grouped according to their immune profile using cluster analysis. RESULTS: TIM3, GTF2I, and XPO1 showed high and consistent expression in the epithelial compartment of TETs across histological subgroups, whereas GITR expression was mostly absent. In the lymphocytic compartment, only XPO1 was highly expressed, with no significant differences between TET subtypes. Epithelial and lymphocytic OX40L expressions were significantly higher in patients with myasthenia gravis (vs. those without this autoimmune disorder; p = 0.004 and p = 0.045, respectively). Importantly, hierarchical clustering identified four distinct TET subgroups based on their combined immune marker expression profiles, which displayed widely divergent survival outcomes (p < 0.0001). Among these, the subgroup characterized by elevated epithelial expression of GTF2I, XPO1, and TIM3 showed worse survival in our multivariate model (HR 6.37; p = 0.025). CONCLUSIONS: TIM3, GTF2I, and XPO1 are highly expressed in the epithelial compartment of TETs, providing a rationale for therapeutic targeting in future immunotherapy trials. Differential IHC expression of TIM3, OX40L, GTF2I, XPO1, and GITR defines distinct TET subtypes with independent prognostic relevance, enabling more accurate risk assessment in these highly heterogeneous thoracic malignancies.