髓系细胞STAT3在肝细胞癌微环境中可抑制抗肿瘤免疫反应

Nonresolving inflammation is a hallmark of cancer and transcription factor STAT3 is a key connection between them. Our recent work reveals that hepatocyte STAT3 accelerates hepatocarcinogenesis induced by a single injection of diethylnitrosamine (DEN). As oncogenic and proinflammatory effects of hepatocyte STAT3 in HCC were expected, it's easy to understand decreased liver tumor formation in DEN treated hepatocyte STAT3 deficient mice. To our surprise, we unexpectedly discovered suppressed liver tumor development in DEN-treated myeloid cells STAT3 deficient mice with enhanced liver inflammation. We further revealed that higher natural killer T cells expansion in liver tumor microenvironment of DEN-treated myeloid cells specific STAT3 knockout mice when compared with that in the wild-type mice. Based on these results, we hypothesize that deletion STAT3 in myeloid cells will disrupt the immune suppressive networks in liver tumor microenvironment, and as a result STAT3 in myeloid cells is an effective target for convert the immune suppression to antitumor immunity. To test our hypothesis, we will first determine which chemokines released by STAT3 knockout myeloid cells are crucial for the accumulation of NKT cells. We further propose to test whether deletion of STAT3 in myeloid cells affects other antitumor immune responses including NK cells, CD8 T cells, Tregs in various animal HCC model and in human HCC patients. If our hypothesis is correct, finally, whether combination standard chemotherapy with STAT3 inhibitor enhances the efficacy in the treatment of HCC using in vitro and in vivo. We anticipate that results from the proposed studies will provide exciting new directions for future myeloid cell-based cancer immunotherapy or combination with chemotherapy.

核转录因子STAT3是连接炎症和肿瘤的关键节点。前期发现肝细胞STAT3致癌致炎作用可促进二乙基亚硝胺(DEN)诱导肝细胞癌（HCC）的发生。敲除髓系细胞STAT3可显著加重肝脏炎症状态，但出乎预想的是，亦同时抵抗DEN的致HCC作用。进一步研究发现降低的HCC与肿瘤微环境中自然杀伤T(NKT)细胞数量明显增加有关。我们推断抑制髓系细胞STAT3表达可打破肝肿瘤微环境的免疫抑制状态，促使其向抗肿瘤免疫反应方向转化。本课题拟首先需找STAT3敲除髓系细胞释放何种化学趋化因子导致NKT细胞的聚集；随后研究拮抗髓系细胞STAT3引发的抗肿瘤免疫反应机制包括其对NK、CD8+T细胞和 Tregs的影响，并拟在临床HCC确认类似机制；最后验证联合使用化疗与STAT3抑制剂是否可以显著抬高治疗效果。本课题研究将为建立髓系细胞为基础的免疫治疗或者联合使用化疗药应用于HCC 的治疗提供理论依据和实验数据。

核转录因子STAT3是连接炎症和肿瘤的关键节点。我们前期发现肝细胞STAT3致癌致炎作用可促进二乙基亚硝胺(DEN)诱导肝细胞癌（HCC）的发生。敲除髓系细胞STAT3亦可抵抗DEN的致HCC作用。进一步研究发现降低的HCC与肿瘤微环境中自然杀伤T(NKT)细胞数量增加和功能增强有关。而在慢性脂肪性肝纤维化恶性化过程中，IL-6-STAT3-miR200a通路亦发挥了重要作用。给予野生型和IL-6基因敲除（KO）小鼠长达1年的高脂肪饮食喂养，结果发现IL-6KO 小鼠有严重的肝损伤和脂肪变性，但是炎症和肿瘤的发生率反而减少，机制研究发现miR200a参与其中。上述研究提示IL-6/STAT3通路发挥了抗肝损伤脂肪变性作用，同时导致炎症和肿瘤的发生。