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
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
复制标题
受体相互作用蛋白激酶3缺陷通过趋化因子（C-X-C基序）配体1 - 趋化因子（C-X-C基序）受体2轴，将髓源抑制细胞募集至肝细胞癌。
DOI：
10.1002/hep.30676
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发表时间：
2019-07-17
期刊：
影响因子：
13.5
通讯作者：
Chen, Zhi-Nan
中科院分区：
文献类型：
--
作者：
Li, Yi-Ming;Liu, Zhen-Yu;Chen, Zhi-Nan
受体相互作用蛋白激酶3（RIP 3）是将细胞死亡从凋亡转变为坏死的核心调节因子。然而，其在肿瘤免疫中的作用尚不清楚。在这项研究中，在肝细胞癌（HCC）患者中观察到RIP 3表达降低，这与髓源性抑制细胞（MDSC）积累相关。此外，RIP 3是肝癌患者的预后因素。我们进一步发现，RIP 3敲低导致肝癌组织中MDSC的增加和干扰素γ阳性（IFN-γ（+））分化簇8阳性（CD 8（+））肿瘤浸润淋巴细胞（IFN-γ（+）CD 8（+）T细胞）的减少，从而促进免疫活性小鼠的免疫逃逸和HCC生长。RIP 3通过磷酸化P65（Ser 536）和促进磷酸化P65（Ser 536）核转位，在HCC细胞中敲低RIP 3增加趋化因子（C-X-C基序）配体1（CXCL 1）的表达。RIP 3敲低通过CXCL 1-趋化因子（C-X-C基序）受体2（CXCR 2）轴诱导MDSC募集。此外，CXCR 2拮抗剂基本上抑制RIP 3敲除小鼠中MDSC趋化性和HCC生长。结论：RIP 3缺陷是指导MDSC归巢至HCC并促进CXCL 1/CXCR 2诱导的MDSC趋化以促进HCC免疫逃逸和HCC进展的重要因素;阻断CXCL 1-CXCR 2趋化因子轴可能提供抑制RIP 3缺陷HCC进展的免疫治疗方法。
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-gamma(+)) cluster of differentiation 8-positive (CD8(+)) tumor-infiltrating lymphocytes (IFN-gamma(+) CD8(+) T cells) in hepatoma tissues, thus promoting immune escape and HCC growth in immunocompetent mice. By phosphorylating P65(Ser536) and promoting phosphorylated P65(Ser536) 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.