Receptor‐Interacting Protein Kinase 3 Deficiency Recruits Myeloid‐Derived Suppressor Cells to Hepatocellular Carcinoma Through the Chemokine (C‐X‐C Motif) Ligand 1–chemokine (C‐X‐C Motif) Receptor 2 Axis
HEPATOLOGY(2019)
Abstract
Receptor‐interacting protein kinase 3 (RIP3) is the core regulator that switches cell death from apoptosis to necrosis. However, its role in tumor immunity is unknown. In this study, decreased RIP3 expression was observed in patients with hepatocellular carcinoma (HCC), which correlates with myeloid‐derived suppressor cell (MDSC) accumulation. Moreover, RIP3 is a prognosis factor for patients with HCC. We further found that RIP3 knockdown results in an increase of MDSCs and a decrease of interferon gamma–positive (IFN‐γ+) cluster of differentiation 8–positive (CD8+) tumor‐infiltrating lymphocytes (IFN‐γ+ CD8+ T cells) in hepatoma tissues, thus promoting immune escape and HCC growth in immunocompetent mice. By phosphorylating P65Ser536 and promoting phosphorylated P65Ser536 nuclear translocation, RIP3 knockdown increases the expression of chemokine (C‐X‐C motif) ligand 1 (CXCL1) in HCC cells. RIP3 knockdown induces MDSC recruitment through the CXCL1–chemokine (C‐X‐C motif) receptor 2 (CXCR2) axis. Furthermore, a CXCR2 antagonist substantially suppresses MDSC chemotaxis and HCC growth in RIP3 knockout mice. Conclusion: RIP3 deficiency is an essential factor directing MDSC homing to HCC and promoting CXCL1/CXCR2‐induced MDSC chemotaxis to facilitate HCC immune escape and HCC progression; blocking the CXCL1–CXCR2 chemokine axis may provide an immunological therapeutic approach to suppress progression of RIP3 deficiency HCC.
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Key words
Immune Regulation,Myeloid-derived suppressor cells,Chemokine Receptors,Cancer Immunotherapy,apoptotic cells
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