A novel Tc17 population recruited by tumor cells promotes tumor progression in gastric cancer.

OBJECTIVE

The tumor microenvironment (TME) plays a crucial role in tumor progression. Recent advancements in single-cell sequencing technology have identified Tc17 cells, a newfound subset of CD8 T cells with a phenotype similar to Th17, within the gastric cancer (GC) microenvironment. However, the role of Tc17 cells are unclear.

MATERIALS AND METHOD

We collected 296,879 cells from the single-cell sequencing data of 65 GC samples, along with spatial transcriptomic data from 10 GC samples, to further explore the role of Tc17 cells. Multicolor immunohistochemical staining demonstrated the presence of Tc17 cells in the GC TME. SCENIC analysis was performed to identify the specific transcription factors of Tc17. Pseudotime analysis of T cells was conducted to decipher the differentiation trajectory of Tc17. Additionally, cell-cell interaction analysis revealed the interactions between Tc17 cells and tumor cells. Finally, functional validation through CCK-8 proliferation assays, wound Healing assays, and transwell assays conclusively demonstrated the tumor-promoting effects of IL-17A and IL-26 on gastric tumor cells.

RESULTS

Our results indicate that Tc17 cells are absent from blood and exclusively found in tissues, with greater enrichment in tumor tissues compared to normal tissues. Among CD8 T cells, Tc17 exhibits the weakest cytotoxic capacity and the highest anti-inflammatory profile, suggesting reduced tumor-killing ability. Pseudotime analysis revealed that Tc17 cells ultimately progress towards a state of exhaustion, losing their capacity to eliminate tumor cells. Survival analysis further correlates the presence of Tc17 cells with poor prognosis. Notably, a robust interaction between Tc17 cells and tumor cells was observed in GC. We found that tumor cells can recruit Tc17 cells via the CXCL16-CXCR6 axis, this finding was validated on spatial transcriptome data. And in turn, Tc17 cells may promote tumor progression by secreting IL-17A and IL-26, as functionally corroborated by CCK-8 Assay, wound healing, and transwell assay .

CONCLUSIONS

These findings reveal the immunosuppressive role of Tc17 cells in gastric cancer, provide a new perspective for understanding the immunosuppressive mechanism of the gastric cancer tumor microenvironment, and provide a potential target for the development of targeted therapeutic strategies.