1. Academic Validation
  2. Postoperative plasmacytoid dendritic cells secrete IFN-α to promote recruitment of myeloid-derived suppressor cells and drive hepatocellular carcinoma recurrence

Postoperative plasmacytoid dendritic cells secrete IFN-α to promote recruitment of myeloid-derived suppressor cells and drive hepatocellular carcinoma recurrence

  • Cancer Res. 2022 Sep 14;CAN-22-1199. doi: 10.1158/0008-5472.CAN-22-1199.
Li Pang 1 Oscar W H Yeung 1 Kevin T P Ng 1 Hui Liu 1 Jiye Zhu 1 Jiang Liu 1 Xinxiang Yang 2 Tao Ding 1 Wenqi Qiu 1 Yuewen Wang 1 T L Shirley Chiu 2 Zhiwei Chen 2 Chung Mau Lo 2 Kwan Man 1
Affiliations

Affiliations

  • 1 University of Hong Kong, Hong Kong, China.
  • 2 University of Hong Kong, Hong Kong, Hong Kong.
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. While 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 IFN-α serve as an independent risk factor for tumor recurrence in 100 HCC patients with curative hepatectomy. Plasmacytoid dendritic cells (pDCs), the major source of IFN-α, were activated after surgery and correlated with poor disease-free survival. Functionally, IFN-α was responsible for mobilization of myeloid-derived suppressor cells (MDSC) following hepatic IRI. Conditioned medium from IFN-α treated hepatocytes mediated the migration of MDSCs in vitro. Mechanistically, IFN-α 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 monocytic MDSCs in vivo. Therapeutically, elimination of pDCs, IFN-α, 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 IFN-α-producing pDCs drive CX3CR1+ MDSC recruitment via hepatocyte IRF1/CX3CL1 signaling and lead to tumor recurrence after hepatectomy in HCC. Targeting pDCs and the IFN-α/CX3CL1/CX3CR1 axis could inhibit surgical-stress-induced HCC recurrence by attenuating postoperative immunosuppression.

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