Serum Galectin-9 mirrors immune-evasive microenvironment and predicts early recurrence in hepatocellular carcinoma

Yang Wenjing; Liu Yu; Tian Tongtong; Jin Anli; Liu Te; Chen Wei; Li Tong; Ding Lin; Wang Hao; Pan Baishen; Wang Beili; Zhou Jian; Fan Jia; Yang Xinrong; Guo Wei

doi:10.1016/j.gene.2024.149184

Serum Galectin-9 mirrors immune-evasive microenvironment and predicts early recurrence in hepatocellular carcinoma

Gene. 2024 Dec 18:149184. doi: 10.1016/j.gene.2024.149184. Online ahead of print.

Authors

Yang Wenjing¹, Liu Yu¹, Tian Tongtong¹, Jin Anli¹, Liu Te², Chen Wei¹, Li Tong¹, Ding Lin¹, Wang Hao¹, Pan Baishen³, Wang Beili⁴, Zhou Jian⁵, Fan Jia⁵, Yang Xinrong⁶, Guo Wei⁷

Affiliations

¹ Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
² Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Shanghai Geriatric Institute of Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200031, China.
³ Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, Shanghai, China.
⁴ Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China; Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, Shanghai, China.
⁵ Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China; Cancer Center, Shanghai Zhongshan Hospital, Fudan University, Shanghai, China.
⁶ Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, PR China; Cancer Center, Shanghai Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: yang.xinrong@zs-hospital.sh.cn.
⁷ Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, China; Cancer Center, Shanghai Zhongshan Hospital, Fudan University, Shanghai, China; Department of Laboratory Medicine, Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China; Department of Laboratory Medicine, Wusong Branch, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: guo.wei@zs-hospital.sh.cn.

PMID: 39706231
DOI: 10.1016/j.gene.2024.149184

Abstract

Background: The precise role of Galectin-9, an immune checkpoint protein involved in immune responses, in hepatocellular carcinoma (HCC) remains elusive. Importantly, the prognostic value of serum Galectin-9 has not been clarified, and its association with infiltrating immune characteristics was unclear.

Methods: The association between serum Galectin-9 concentration and HCC recurrence was analyzed in two cohorts of HCC patients (training 133; validation 97) who received curative resection during 2018 and 2019. Bioinformatic analyses, including WGCNA, GSEA, GO, KEGG, Hallmark, CIBERSORT, QUANTISEQ, ssGSEA and TISIDB, were performed to systematically demonstrate the expression pattern, immunomodulation role, and prognostic value of Galectin-9 in HCC. These findings were further validated by immunohistochemistry staining.

Results: Patients with high serum Galectin-9 levels had significantly shorter time to tumor recurrence (TTR; P < 0.001) in both cohorts, and serum Galectin-9 was identified as an independent predictor of HCC recurrence, even in patients with low-AFP or early-stage. Bioinformatic analyzes revealed high Galectin-9 expression involves in immune-evasive and inflammatory signaling pathways. It correlated with increased infiltration of exhausted CD8 + T cells, Tregs, TAMs and MDSCs. Interestingly, we found Galectin-9 was predominantly expressed on macrophages rather than malignant cells, and showed positively association with serum Galectin-9 concentration according to IHC results. Concordantly, high serum Galectin-9 levels also reflected an immune-evasive microenvironment composed by extensive CD163 + and FOXP3 + cell infiltrates.

Conclusions: Elevated serum Galectin-9 was a novel indicator for worse prognosis in HCC. The high expression of Galectin-9 may reflect the immunosuppressive environment by increasing CD163 + and FOXP3 + cell infiltrates.

Keywords: Bioinformatics; Hepatocellular carcinoma; Immune infiltrates; Serum Galectin-9; Tumor recurrence.