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

  • Cancer Lett. 2021 May 28:506:95-106. doi: 10.1016/j.canlet.2021.03.002.
Yihe Yan  1 ,  Leting Zheng  2 ,  Qiang Du  3 ,  Hamza Yazdani  3 ,  Kun Dong  3 ,  Yarong Guo  3 ,  David A Geller  4
Affiliations
  • 1. Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530007, China; Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA. Electronic address: [email protected].
  • 2. Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA; Department of Rheumatology and Immunology, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, 530021, China.
  • 3. Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA.
  • 4. Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA. Electronic address: [email protected].
PMID: 33689775 DOI: 10.1016/j.canlet.2021.03.002
Abstract

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.

Keywords
Chemokine; Chemokine receptor; Hepatocellular carcinoma; IRF-1; Tumor microenvironment.
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