Postoperative Plasmacytoid Dendritic Cells Secrete IFNa to Promote Recruitment of Myeloid-Derived Suppressor Cells and Drive Hepatocellular Carcinoma Recurrence

Abstract

Patients with hepatocellular carcinoma (HCC) confront a high incidence of tumor recurrence after curative surgical resection. Hepatic ischemia-reperfusion injury (IRI) is the major consequence of surgical stress during hepatectomy. Although it has been suggested that hepatic IRI-induced immunosuppression could contribute to tumor relapse after surgery, the underlying mechanisms have not been fully defined. Here, using a multiplex cytokine array, we found that levels of postoperative IFNa serve as an independent risk factor for tumor recurrence in 100 patients with HCC with curative hepatectomy. Plasmacytoid dendritic cells (pDC), the major source of IFNa, were activated after surgery and correlated with poor disease-free survival. Functionally, IFNa was responsible for mobilization of myeloid-derived suppressor cells (MDSC) following hepatic IRI. Conditioned medium from IFNa-treated hepatocytes mediated the migration of MDSCs in vitro. Mechanistically, IFNa upregulated IRF1 to promote hepatocyte expression of CX3CL1, which subsequently recruited CX3CR1 monocytic MDSCs. Knockdown of Irf1 or Cx3cl1 in hepatocytes significantly inhibited the accumulation of monocyticMDSCs in vivo. Therapeutically, elimination of pDCs, IFNa, or CX3CR1 could restore the tumor-killing activity of CD8 T cells, hence limiting tumor growth and lung metastasis following hepatic IRI. Taken together, these data suggest that IFNa-producing pDCs drive CX3CR1 MDSC recruitment via hepatocyte IRF1/CX3CL1 signaling and lead to tumor recurrence after hepatectomy in HCC. Targeting pDCs and the IFNa/CX3CL1/CX3CR1 axis could inhibit surgical stress-induced HCC recurrence by attenuating postoperative immunosuppression.