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TDO2+ myofibroblasts mediate immune suppression in malignant transformation of squamous cell carcinoma

Aug.22,2022

Prof. Fan Bai published a paper in The Journal of Clinical Investigation with his collaborator.


Characterization of the dynamic change of immunological landscape during malignant transformation from precancerous lesion to cancerous lesion in squamous cell carcinoma (SCC) is critical for the application of immunotherapy. Here we performed single-cell RNA sequencing (scRNA-seq) of 131,702 cells from 13 cancerous tissues of oral squamous cell carcinoma (OSCC), 3 precancerous oral leukoplakia and 8 adjacent normal samples. We revealed that 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, we identified a subset of myofibroblasts that exclusively expressed tryptophan 2,3-dioxygenase (TDO2). These TDO2myofibroblast 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. We further showed that the use of TDO2 inhibitor LM10 attenuated the inhibitory states of T cells, restored T cells anti-tumor response and prevented the progression of OSCC malignant transformation in murine models. Our study provides a multi-step transcriptomic landscape of OSCC and demonstrates that TDO2+ myofibroblasts are potential targets for immunotherapy.


Original link: https://www.jci.org/articles/view/157649.