IADR Abstract Archives
TDO2+ Myofibroblasts Mediate Immune Suppression in Malignant Transformation of OSCC
Objectives: To characterize the dynamic change of immunological landscape during malignant transformation from precancerous lesion to cancerous lesion in OSCC.
Methods: We 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; multiplex immunohistochemical staining to analyze the spatial localization of TDO2+/TDO2- myofibroblasts and cancer cells; High-content cell imaging to show the difference between the CXCR3+CD3+ T cell chemoattractant abilities of TDO2+/TDO2- myofibroblasts; the co-culture system to determine whether TDO2+ myofibroblasts exert an immune regulatory upon T cells; immunohistochemistry staining of the tissue microarrays from 142 OSCC patients for survival analyses; furthermore, we used the 4NQO-induced carcinogenesis model to examine the effects of TDO2 inhibitors on OSCC in vivo.
Results: 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 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. We 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.
Conclusions: Our study provides a multi-step transcriptomic landscape of OSCC and demonstrates that TDO2+ myofibroblasts are potential targets for immunotherapy.
Methods: We 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; multiplex immunohistochemical staining to analyze the spatial localization of TDO2+/TDO2- myofibroblasts and cancer cells; High-content cell imaging to show the difference between the CXCR3+CD3+ T cell chemoattractant abilities of TDO2+/TDO2- myofibroblasts; the co-culture system to determine whether TDO2+ myofibroblasts exert an immune regulatory upon T cells; immunohistochemistry staining of the tissue microarrays from 142 OSCC patients for survival analyses; furthermore, we used the 4NQO-induced carcinogenesis model to examine the effects of TDO2 inhibitors on OSCC in vivo.
Results: 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 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. We 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.
Conclusions: Our study provides a multi-step transcriptomic landscape of OSCC and demonstrates that TDO2+ myofibroblasts are potential targets for immunotherapy.