Intrathymic dendritic cells contribute to immune dysregulation in thymic epithelial tumors

Thymic epithelial tumors (TETs) are rare mediastinal tumors that include thymomas (subtypes A, AB, B1, B2 and B3) and thymic carcinomas (TC)s. Type AB and B thymomas are characterized by active intratumor thymopoiesis and a strong association with autoimmune disorders (ADs), suggesting a potential link between specific histological subtypes and immune dysregulation. Dendritic cells (DCs) are key regulators of thymic central tolerance, yet their contribution to AD development in TETs remains poorly understood. To investigate the role of DCs in TET-associated immune dysregulation, we characterized the transcriptomic profile of intratumor DCs by performing single-cell RNA sequencing of 19 TETs subdivided in different histotypes, compared with 4 healthy donors. By applying consolidated gene signatures, we identified different subsets of thymic DCs, including plasmacytoid DCs (pDCs), transitional DCs (tDCs), conventional DC1s (cDC1s), and cDC2s, and compared their gene expression profile across TET subtypes. pDCs were the predominant DC subset in healthy thymuses and thymomas with active thymopoiesis. However, pDCs in type B1 and B2 thymomas, which are the TETS with the strongest association with ADs, showed a reduced activation of the IL-23–STAT3–type I interferon (IFN) axis, with a lower expression of STAT3 downstream regulators. Moreover, DCs, thymocytes and B cells from thymomas showed reduced IFN responsiveness, as assessed by decreased expression of IFN-stimulated-genes. Because of the essential role of IFN in central tolerance, our results may suggest that an attenuation of thymic IFN signaling may contribute to immune dysregulation and AD development in thymomas. Accordingly, preliminary data from our group revealed a profound defect in thymic Treg generation in these tumors. Ongoing analyses of the other DC subsets are revealing changes associated with specific TET histotypes, altogether providing a mechanistic framework linking DCs to defective thymic tolerance in thymomas and immunoregulatory metabolic adaptation in TCs.