The study performed scRNA-seq from 13 cancerous tissues of OSCC, 3 precancerous oral leukoplakia and 8 adjacent normal samples to systematically survey the cellular diversity of malignant transformation during oral carcinogenesis. Tumor infiltrating CD4+ and CD8+ T cells were functionally inhibited by immunosuppressive ligands expressed on various kinds of myeloid cells or neutrophils in the process of oral carcinogenesis. Notably, the study identified a subset of myofibroblasts that exclusively expressed TDO2, and TDO2 was predominantly expressed in α-SMA+ myofibroblasts in OSCC, whereas it was nearly absent in normal tissues or in tumor cells. These TDO2+ myofibroblast were located distally from tumor nests and both CD4+ and CD8+ T cells were enriched around them. Functional experiments revealed that TDO2+ myofibroblasts were more likely to possess the chemotactic ability for T cells, but induced transformation of CD4+ T cells into regulatory T cells and caused CD8+ T cell dysfunction. Survival analyses reveal that TDO2+ myofibroblasts are associated with a worse prognosis for OSCC patients. The study further showed that the use of TDO2 inhibitor LM10 attenuated the inhibitory states of T cells, re-activated its anti-tumor response and prevented the progression of OSCC malignant transformation in murine models. The study provides a multi-step transcriptomic landscape of OSCC and demonstrates that TDO2+ myofibroblasts are potential targets for immunotherapy.
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