myofibroblasts mediate immune suppression in malignant transformation of squamous cell carcinoma

Characterization of the dynamic change in the immunological landscape during malignant transformation from precancerous lesions to cancerous lesions in squamous cell carcinoma (SCC) is critical for the application of immunotherapy. Here, we performed single-cell RNA-Seq (scRNA-Seq) of 131,702 cells from 13 cancerous tissues of oral squamous cell carcinoma (OSCC), 3 samples of precancerous oral leukoplakia, and 8 adjacent normal samples. We found that tumor-infiltrating [CD4.sup.+] and [CD8.sup.+] T cells were functionally inhibited by immunosuppressive ligands expressed on various types 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 [TDO2.sup.+] myofibroblasts were located distally from tumor nests, and both [CD4.sup.+] and [CD8.sup.+] T cells were enriched around them. Functional experiments revealed that [TDO2.sup.+] myofibroblasts were more likely to possess the ability for chemotaxis toward T cells but induced the transformation of [CD4.sup.+] T cells into Tregs and caused [CD8.sup.+] T cell dysfunction. We further showed that use of the TDO2 inhibitor LM10 attenuated the inhibitory states of T cells, restored the T cell antitumor response, and prevented the progression of OSCC malignant transformation in murine models. Our study reveals a multistep transcriptomic landscape of OSCC and demonstrates that [TDO2.sup.+] myofibroblasts are potential targets for immunotherapy.
Introduction Oral squamous cell carcinoma (OSCC), a malignancy that occurs in the epithelium of the oral cavity, is the predominant type of head and neck squamous cell carcinoma (HNSCC). It [...]