Prognostic value and potential upstream regulator of Th17 cells in esophageal squamous cell carcinoma

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Esophageal squamous cell carcinoma (ESCC), a malignant tumor of the digestive tract, exhibits high incidence and mortality rates. The emergence of cancer immunotherapy necessitates urgent investigation into immune-related mechanisms in ESCC and other malignancies. Utilizing TCGA data from 93 ESCC patients and two Gene Expression Omnibus (GEO) datasets, we identified target immune cells via single-sample gene set enrichment analysis (ssGSEA) and established a prognostic prediction model. Weighted gene co-expression network analysis (WGCNA) screened relevant genes, while the TIMER database analyzed associated signaling pathways. Using ESCC tissue sections from our institutional cohort of 110 patients, the expression levels of relevant proteins were evaluated by immunohistochemistry (IHC), and correlation analyses were performed to further assess these findings. Th17 cell infiltration was associated with poor prognosis in ESCC patients ( P < 0.05). The nomogram showed favorable predictive performance, with a C-index of 0.808 (95% CI: 0.715–0.900). In the institutional cohort, high RAR-related orphan receptor C (RORC) expression was associated with poorer survival ( P = 0.002), and RORC IHC score was identified as a prognostic risk factor (HR = 1.32, 95% CI: 1.07–1.63; P = 0.009). Kruppel-like transcription factor 7 (KLF7) expression correlated with interleukin-6 receptor (IL6R), interleukin-1 receptor type 1 (IL1R1), signal transducer and activator of transcription 3 (STAT3), and RORC expression in ESCC and other malignancies. IHC analysis further demonstrated positive correlations among KLF7, STAT3, and RORC expression in ESCC tissues. Functional assays showed that KLF7 knockdown reduced KLF7 and STAT3 expression in ESCC cells and suppressed Th17 cell proliferation. These findings suggest that Th17/RORC-related immune features have prognostic value in ESCC and that KLF7 may be involved in STAT3-associated Th17-related immune regulation.

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