Abnormal Cellular Populations Shape Thymic Epithelial Tumor Heterogeneity and Anti-Tumor by Blocking Metabolic Interactions in Organoids

A variety of abnormal epithelial cells and immature and mature immune cells in thymic epithelial tumors (TETs) affect histopathological features, the degree of malignancy, and the response to treatment. Here, gene expression, trajectory inference, and T cell antigen receptor (TCR)-based lineage tracking are profiled in TETs at single-cell resolution. An original subpopulation of KRT14 progenitor cells with a spindle cell phenotype is shown. An abnormal infiltration of immature T cells with a TCR hyper-rearrangement state is revealed, due to the lack of CCL21 medullary epithelial cells. For thymic carcinoma, the novel biomarkers of MSLN, CCL20, and SLC1A5 are identified and observed an elevated expression of LAG3 and HAVCR2 in malignant tumorn-infiltrating mature T cells. These common features based on the single-cell populations may inform pathological reclassification of TETs. Meanwhile, it is found that macrophages (MACs) attract thymic tumor cells through the LGALS9-SLC1A5 axis, providing them with glutamine to elicit metabolic reprogramming. This MAC-based metabolic pattern can promote malignancy progression. Additionally, an interactive immune environment in TETs is identified that correlates with the infiltration of abnormal FOXI1 CFTR ionocytes. Collectively, the data broaden the knowledge of TET cellular ecosystems, providing a basis for tackling histopathological diagnosis and related treatment.