Interferon regulatory factor 1(IRF-1) activates anti-tumor immunity via CXCL10/CXCR3 axis in hepatocellular carcinoma (HCC)

• Published in: Cancer letters 2021-05, Vol.506, p.95-106
• Main Authors: Yan, Yihe, Zheng, Leting, Du, Qiang, Yazdani, Hamza, Dong, Kun, Guo, Yarong, Geller, David A.
• Format: Article
• Language: English
• Subjects: Antibodies; Apoptosis; Autocrine signalling; Cancer therapies; CD8 antigen; Cell migration; Cell proliferation; Chemokine; Chemokine receptor; Chemokine receptors; Chemokines; Cloning; CXCL10 protein; CXCR3 protein; Flow cytometry; Gene expression; Hepatocellular carcinoma; Immunity (Disease); Interferon regulatory factor; Interferon regulatory factor 1; IRF-1; Liver cancer; Lymphocytes T; Natural killer cells; Paracrine signalling; Proteins; Regulatory sequences; Transcription; Tumor microenvironment; Tumor suppressor genes; Tumors; γ-Interferon
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2021.03.002

Interferon regulatory factor 1 (IRF-1) is a tumor suppressor gene in cancer biology with anti-proliferative and pro-apoptotic effect on cancer cells, however mechanisms of IRF-1 regulating tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remain only partially characterized. Here, we investigated that IRF-1 regulates C-X-C motif chemokine 10 (CXCL10) and chemokine receptor 3 (CXCR3) to activate anti-tumor immunity in HCC. We found that IRF-1 mRNA expression was positively correlated with CXCL10 and CXCR3 through qRT-PCR assay in HCC tumors and in analysis of the TCGA database. IRF-1 response elements were identified in the CXCL10 promoter region, and ChIP-qPCR confirmed IRF-1 binding to promote CXCL10 transcription. IRF-2 is a competitive antagonist for IRF-1 mediated transcriptional effects, and overexpression of IRF-2 decreased basal and IFN-γ induced CXCL10 expression. Although IRF-1 upregulated CXCR3 expression in HCC cells, it inhibited proliferation and exerted pro-apoptotic effects, which overcome proliferation partly mediated by activating the CXCL10/CXCR3 autocrine axis. In vitro and in vivo studies showed that IRF-1 increased CD8+ T cells, NK and NKT cells migration, and activated IFN-γ secretion in NK and NKT cells to induce tumor apoptosis through the CXCL10/CXCR3 paracrine axis. Conversely, this effect was markedly abrogated in HCC tumor bearing mice deficient in CXCR3. Therefore, the IRF-1/CXCL10/CXCR3 axis contributes to the anti-tumor microenvironment in HCC. •IRF-1 promotes CXCL10 expression at the transcriptional level by binding to specific IRF-1 response elements in the CXCL10 promoter.•IRF-1 upregulates CXCR3 expression in HCC cells.•IRF-1 exerts anti-proliferative and pro-apoptotic effects on HCC cells, which overcomes proliferation partly mediated by activating the CXCL10/CXCR3 autocrine axis.•IRF-1 increases NK, NKT, and CD8+ T cells enrichment, and activates IFN-γ secretion in NK and NKT cells through the CXCL10/CXCR3 paracrine axis.