Targeting tumor-infiltrating Ly6G+ myeloid cells improves sorafenib efficacy in mouse orthotopic hepatocellular carcinoma
Targeting tumor-infiltrating Ly6G+ myeloid cells improves sorafenib efficacy in mouse orthotopic hepatocellular carcinoma
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DOI：
10.1002/ijc.31216
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发表时间：
2018-05-01
影响因子：
6.4
通讯作者：
Cheng, Ann-Lii
中科院分区：
文献类型：
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作者：
Chang, Chun-Jung;Yang, Yao-Hsu;Cheng, Ann-Lii
索拉非尼是一种具有抗血管生成活性的多激酶抑制剂，已被批准用于治疗肝细胞癌（HCC）。目前尚不清楚促炎和免疫抑制机制是否会限制索拉非尼在HCC中的治疗效果。我们使用同基因小鼠肝癌细胞系建立原位肝或皮下肿瘤，以研究促炎和免疫抑制机制如何影响索拉非尼的疗效。我们发现索拉非尼在皮下肿瘤中表现出有效的治疗作用，但在原位肝肿瘤中的作用较弱。索拉非尼治疗后，原位肝肿瘤中白细胞介素-6（IL-6）和血管内皮生长因子A（VEGF-A）的蛋白水平持续升高，但皮下肿瘤中没有。同样，索拉非尼治疗后，原位肝肿瘤中肿瘤浸润的Ly 6 G（+）骨髓源性抑制细胞（MDSC）和免疫抑制细胞增加，而皮下肿瘤中没有。索拉非尼处理的原位肝肿瘤的肿瘤浸润性Ly 6 G（+）MDSC显著诱导表达IL-10和TGF-β的CD 4（+）T细胞，并下调CD 8（+）T细胞的细胞毒活性。IL-6，而不是VEGF-A，在体外保护Ly 6 G（+）MDSC免于索拉非尼诱导的细胞死亡。抗Ly 6 G抗体或抗IL-6抗体与索拉非尼联合应用可显著降低原位肝肿瘤中Ly 6 G（+）MDSC的细胞比例，促进T细胞增殖，协同提高索拉非尼的治疗效果。通过靶向肿瘤浸润的Ly 6 G（+）MDSC来调节肿瘤微环境是提高索拉非尼抗肝癌疗效的潜在策略。多激酶抑制剂索拉非尼是批准用于治疗肝癌的药剂。使用同基因小鼠肝癌模型，作者发现索拉非尼在原位肝肿瘤中的治疗效果低于皮下肿瘤。他们将此归因于原位肿瘤中发现的促炎细胞因子和免疫抑制性骨髓源性抑制细胞水平的增加，当抑制时，索拉非尼的治疗效率增加。作者提出靶向免疫抑制肿瘤微环境作为肝癌的新治疗方法。
Sorafenib, a multikinase inhibitor with antiangiogenic activity, is an approved therapy for hepatocellular carcinoma (HCC). It is unclear whether the proinflammatory and immunosuppressive mechanisms may limit the therapeutic efficacy of sorafenib in HCC. We used a syngeneic mouse liver cancer cell line to establish orthotopic liver or subcutaneous tumors to study how proinflammatory and immunosuppressive mechanisms impact on the efficacy of sorafenib. We found sorafenib exhibited a potent therapeutic effect in subcutaneous tumors, but a less potent effect in orthotopic liver tumors. The protein levels of interleukin-6 (IL-6) and vascular endothelial growth factor A (VEGF-A) were persistently elevated in orthotopic liver tumors, but not in subcutaneous tumors, treated with sorafenib. Likewise, the tumor-infiltrating Ly6G(+) myeloid-derived suppressor cells (MDSCs) and immune suppressors were increased in orthotopic liver tumors, not in subcutaneous tumors, treated with sorafenib. The tumor-infiltrating Ly6G(+) MDSCs of sorafenib-treated orthotopic liver tumors significantly induced IL-10 and TGF- expressing CD4(+) T cells, and downregulated the cytotoxic activity of CD8(+) T cells. IL-6, but not VEGF-A, protected Ly6G(+) MDSCs from sorafenib-induced cell death in vitro. The combination of anti-Ly6G antibody or anti-IL-6 antibody with sorafenib significantly reduced the cell proportion of Ly6G(+) MDSCs in orthotopic liver tumors, enhanced the T cells proliferation and improved the therapeutic effect of sorafenib synergistically. Modulating tumor microenvironment through targeting tumor-infiltrating Ly6G(+)MDSCs represents a potential strategy to improve the anti-HCC efficacy of sorafenib.What's new?The multi-kinase inhibitor sorafenib is an approved agent for the treatment of liver cancer. Using a syngeneic mouse liver cancer model, the authors found less therapeutic efficacy of sorafenib in orthotopic liver tumors as compared to subcutaneous tumors. They attributed this to increased levels of proinflammatory cytokines and immunosuppressive myeloid-derived suppressor cells found in orthotopic tumors, conditions that when suppressed increased sorafenib's therapeutic efficiency. The authors propose targeting the immunosuppressive tumor microenvironment as a novel therapeutic approach for liver cancers.