Molecular imprint of epithelial origin identifies immuno-subtype of thymic epithelial tumors

Abstract Thymic epithelial tumors (TETs) are common tumors in human anterior mediastinum with limited biological understanding. Through decoding the immune landscape of tumors, we reclassify TETs into three types based on T cell developmental patterns. We uncover the developmental dysfunction and TCR repertoire of tumor-infiltrating T cells by cell atlas. Moreover, we identify the unique subset of tumor cells with distinct epithelial origin in each TETs type. Furthermore, we demonstrate that KRT14/GNB3+ mTECs-like cell accumulation inhibits the T cell positive selection in type 1 TETs, while CCL25+ cTEC-like cell promotes T cell positive selection in type 2. Interestingly, although CHI3L1+ mTEC-like cell in type 3 TETs loses the function of supporting T cell development, it acquires the capacity to induce CD8+TRMs-mediated response. Finally, we propose a new molecular classification of human TETs using GNB3 and CHI3L1 to distinguish the epithelial origin of tumor cells, which is promising in prognostic prediction.