Interleukin-35 has a tumor-promoting role in hepatocellular carcinoma

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Abstract
Background Hepatic inflammatory response is a risk factor for liver cancer initiation and progression. Interleukin (IL)‐35 is the newest member of IL‐12 cytokine family, and has been reported to play an essential role in the immunosuppressive liver microenvironment. Herein we focus on the expression profiles of IL‐35 in hepatocellular carcinoma (HCC) and effects on local immune status. Methods HCC transcriptome array data were downloaded from GEO. Analysis was performed by BRB array tools and IPA software. Serum IL‐35 level was detected by AimPlet bead‐based immunoassay. In situ IL‐35 detection was performed by immunohistochemical staining and western blot. In vitro effect of IL‐35 on CD4+ or CD8+ T cell function was detected by flow cytometry. Results Our results showed that there were large amounts of IL‐35 expressed in HCC serum and tumor tissues. IL‐35 expression affects the transcript of thousands of genes, most differentially expressed genes (DEGs) in tumor tissues correlated with T‐cell immunity. The IL‐35 high‐expression group exhibited enhancement of regulatory T cells (Tregs) and impairment of cytolytic T cells. In vitro experiments proved that exogenous IL‐35 stimulated the expression of PD1 and LAG3 in CD4+ and CD8+ T cells. In addition, the stimulating effect was time‐dependent. Furthermore, IL‐35 inhibited interferon(IFN)‐γ secretion by CD4+ and CD8+ T cells. Conclusions Elevated IL‐35 had an immune suppressive role in HCC tumor microenvironments through affecting inhibitor receptor expression and cytokine secretion of CD4+ and CD8+ T cells. Dissection of the precise targets and underlying molecular mechanisms would mean alternative treatments for HCC patients. (250 words)
Funding Information
  • Natural Science Foundation of Tianjin Municipality (18JCYBJC26400)

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