IADR Abstract Archives
Delineating Pre-Metastatic Niche Formation in Lymph Nodes of OSCC at Single-Cell Perspective
Objectives: Tumor metastasis profoundly impact patient outcome, contributing to poor prognosis and survival rates. While significant research on oral squamous cell carcinoma (OSCC) research has focused on the metastatic behavior of tumor cells, the mechanisms governing pre-metastatic niche (PMN) remains poorly understood. Here, we aimed to explore the formation and development mechanisms of PMN.
Methods: Leveraging single-cell transcriptomics sequencing , we profiled 191,226 high-quality cells (36 cell types) from paired tumors tissue, adjacent tissues, and lymph nodes of OSCC patients with and without LN metastasis. Spatial in situ transcriptomics sequencing was performed to obtain the spatial information of cell types and the interactions between them. In vivo and in vitro experiments were conducted to validate the conclusions derived from our data analysis.
Results: TNC+ cancer-associated fibroblasts interact with EGFR on tumor cells, trigging the PI3K-AKT signaling cascade and upregulating the transcription factor MAZ, which promotes early tumor malignant transformation. These malignant tumor cells subsequently recruit FOLR2+ tumor-associated macrophages via IL-16 secretion, inducing a distinct subset of central memory CD4+ T cell formation. These CD4+ T cells, enriched in pre-metastatic and metastatic lymph nodes, correlate with poor survival outcomes and exhibit cytokine-educated inflammatory phenotypes. Mechanistically, these cells migrate to lymph nodes through CCL5-ACK receptor interaction on lymphatic endothelial cells, where they mediated CD8+ T cells and NK cells exhaustion via prostaglandin signaling, establishing an early immunosuppressive microenvironment. POSTN+ CAFs then infiltrate the lymph node niche, activating central memory CD4+ T cells and promoting their differentiation into effective Tregs, further exacerbating immune suppression.
Conclusions: This study provides a detailed mechanistic framework for PMN formation in OSCC lymph node metastasis, offering critical insights for improving early diagnosis and developing targeted therapeutic strategies.
Methods: Leveraging single-cell transcriptomics sequencing , we profiled 191,226 high-quality cells (36 cell types) from paired tumors tissue, adjacent tissues, and lymph nodes of OSCC patients with and without LN metastasis. Spatial in situ transcriptomics sequencing was performed to obtain the spatial information of cell types and the interactions between them. In vivo and in vitro experiments were conducted to validate the conclusions derived from our data analysis.
Results: TNC+ cancer-associated fibroblasts interact with EGFR on tumor cells, trigging the PI3K-AKT signaling cascade and upregulating the transcription factor MAZ, which promotes early tumor malignant transformation. These malignant tumor cells subsequently recruit FOLR2+ tumor-associated macrophages via IL-16 secretion, inducing a distinct subset of central memory CD4+ T cell formation. These CD4+ T cells, enriched in pre-metastatic and metastatic lymph nodes, correlate with poor survival outcomes and exhibit cytokine-educated inflammatory phenotypes. Mechanistically, these cells migrate to lymph nodes through CCL5-ACK receptor interaction on lymphatic endothelial cells, where they mediated CD8+ T cells and NK cells exhaustion via prostaglandin signaling, establishing an early immunosuppressive microenvironment. POSTN+ CAFs then infiltrate the lymph node niche, activating central memory CD4+ T cells and promoting their differentiation into effective Tregs, further exacerbating immune suppression.
Conclusions: This study provides a detailed mechanistic framework for PMN formation in OSCC lymph node metastasis, offering critical insights for improving early diagnosis and developing targeted therapeutic strategies.