The CAS Key Laboratory of Innate Immunity and Chronic Disease and Institute of Immunology, School of Life Science and Medical Center, University of Science and Technology of China, Hefei, 230027, Anhui, China.
Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, Zhejiang, China.
Nat Commun. 2018 Mar 28;9(1):1241. doi: 10.1038/s41467-018-03584-3.
A chronic viral or tumor microenvironment can push T cells to exhaustion by promoting coinhibitory ligand expression. However, how host factors control coinhibitory ligand expression and whether viral infection breaks this control during tumor progress is unknown. Here we show a close negative correlation between SALL4 or PD-L1 and miR-200c in tumors from 98 patients with HBV-related hepatocellular carcinoma. SALL4 or PD-L1 expression correlates negatively with miR-200c expression, and patients with lower levels of SALL4 or PD-L1 and higher miR-200c survive longer. Moreover, over-expression of miR-200c antagonizes HBV-mediated PD-L1 expression by targeting 3'-UTR of CD274 (encoding PD-L1) directly, and reverses antiviral CD8 T cell exhaustion. MiR-200c transcription is inhibited by oncofetal protein SALL4, which is re-expressed through HBV-induced STAT3 activation in adulthood. We propose that an HBV-pSTAT3-SALL4-miR-200c axis regulates PD-L1. Therapeutic strategies to influence this axis might reverse virus-induced immune exhaustion.
慢性病毒或肿瘤微环境可通过促进共抑制配体表达使 T 细胞衰竭。然而，宿主因素如何控制共抑制配体的表达，以及病毒感染是否在肿瘤进展过程中打破这种控制尚不清楚。在这里，我们在来自 98 例 HBV 相关肝细胞癌患者的肿瘤中发现 SALL4 或 PD-L1 与 miR-200c 之间存在密切的负相关关系。SALL4 或 PD-L1 的表达与 miR-200c 的表达呈负相关，SALL4 或 PD-L1 水平较低且 miR-200c 水平较高的患者存活时间更长。此外，miR-200c 通过直接靶向 CD274（编码 PD-L1）的 3'UTR 拮抗 HBV 介导的 PD-L1 表达，并逆转抗病毒 CD8 T 细胞衰竭。miR-200c 的转录受到癌胚蛋白 SALL4 的抑制，该蛋白通过 HBV 诱导的 STAT3 激活在成年期重新表达。我们提出，HBV-pSTAT3-SALL4-miR-200c 轴调节 PD-L1。影响该轴的治疗策略可能会逆转病毒诱导的免疫衰竭。
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