High INHBB Expression Shapes an Immunosuppressive Tumor Microenvironment and Predicts Poor Prognosis in Colorectal
Hiroshi Sawaguchi1, Takeshi Uehara2, Mai Iwaya3
1Division of Gastroenterology and Hepatology, Department of Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
Background:
Inhibin subunit beta B (INHBB), a member of the TGF-β superfamily, has emerged as a potential regulator of tumor progression and immune modulation. However, its clinical and immunological significance in colorectal cancer (CRC) remains unclear.
Methods:
This study evaluated INHBB mRNA expression in 248 CRC cases using RNA in situ hybridization (RNAscope), immunohistochemistry (IHC), and single-cell RNA sequencing (scRNA-seq). Associations with clinicopathological parameters, tumor-infiltrating immune cells, and prognosis were analyzed.
Results:
INHBB was primarily expressed in tumor epithelial cells and weakly in stromal cells, but was negligible in normal mucosa. High INHBB expression correlated significantly with venous invasion, lymph node metastasis, advanced TNM stage, and reduced tumor-infiltrating lymphocytes. IHC revealed marked decreases in CD4⁺, CD8⁺, and FOXP3⁺ T cells and increased CD163⁺ tumor-associated macrophages in INHBB high tumors, indicating an immunosuppressive tumor microenvironment (TME). Kaplan-Meier analysis showed that high INHBB expression was associated with worse overall survival and recurrence-free survival, but was not an independent prognostic factor in multivariate models.
Conclusion:
INHBB is predominantly expressed in tumor epithelium and is associated with aggressive features, poor prognosis, and the formation of an immune-cold, macrophage-rich TME in CRC. These findings suggest that INHBB may be a potential biomarker for immune evasion and a target for novel immunotherapeutic strategies in CRC.
