Combined blockade of TGf-β1 and GM-CSF improves chemotherapeutic effects for pancreatic cancer by modulating tumor microenvironment
Combined blockade of TGf-β1 and GM-CSF improves chemotherapeutic effects for pancreatic cancer by modulating tumor microenvironment
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联合阻断 TGf-β1 和 GM-CSF 通过调节肿瘤微环境改善胰腺癌化疗效果
DOI：
10.1007/s00262-020-02542-7
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发表时间：
2020-04-13
影响因子：
5.8
通讯作者：
Zhao, Yupei
中科院分区：
文献类型：
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作者：
Liu, Qiaofei;Wu, Huanwen;Zhao, Yupei
肿瘤免疫微环境（TIME）和胰腺癌细胞之间的相互作用可以影响化疗效果;然而，其机制仍然在很大程度上未知。应用胰腺癌组织芯片对TIME中的30个项目进行综合筛选。分析了它们的表达、相互联系和对生存的预测作用。30项指标中有21项可对患者的生存进行分层;然而，多变量分析发现，只有5个独立的危险因素可预测较差的生存（M2极化肿瘤相关巨噬细胞（TAM），IgG 4阳性细胞，TGF-β1，GM-CSF和淋巴管生成）。与瘤周组织相比，它们在肿瘤组织中具有高得多的表达水平。斯皮尔曼分析显示，M2极化TAM、TGF-β1和GM-CSF与胰腺癌干细胞（PCSC）、血管生成和淋巴管生成呈正相关。人胰腺癌细胞和小鼠胰腺癌细胞均能诱导出M2极化的TAM，其对化疗效果有明显的抑制作用。经吉西他滨处理后，人和小鼠胰腺癌细胞株均表达较高水平的免疫检查点、PCSC标志物和多种免疫抑制因子，但以TGF-β1和GM-CSF的表达最高。基于上述结果，TGF-β1和GM-CSF被认为是改善化疗效果的最佳潜在靶点。在免疫活性小鼠模型中，我们证明了TGF-β1和GM-CSF的联合阻断通过抑制M2极化TAM和诱导CD 8阳性T细胞来改善化疗效果。本研究提出了一种新的有前途的联合策略，以提高胰腺癌的化疗效果。
The interactions between tumor immune microenvironment (TIME) and pancreatic cancer cells can affect chemotherapeutic efficacy; however, the mechanisms still remain largely unknown. Thirty items in TIME were comprehensively screened by using tissue microarray from pancreatic cancer patients. Their expressions, interconnections and predictive roles for survival were analyzed. Twenty-one of 30 items could stratify the survival of the patients; however, multivariate analysis found that only 5 independent risk factors could predict worse survival (M2-polarized tumor-associated macrophages (TAMs), IgG4 positive cells, TGF-β1, GM-CSF and lymphangiogenesis). They had a much higher expression levels in tumoral tissue, compared to peritumoral tissue. The Spearman analysis showed that M2-polarized TAM, TGF-β1 and GM-CSF were positively correlated with pancreatic cancer stem cells (PCSC), angiogenesis and lymphangiogenesis. Both human and murine pancreatic cancer cells could induce M2-polarized TAM, which showed substantial roles to decease chemotherapeutic effects. After treated by gemcitabine, both human and murine pancreatic cancer cell lines expressed higher level of immune check points, PCSC markers and varieties of immunosuppressive factors; however, TGF-β1 and GM-CSF had the highest increase. Based on the above results, TGF-β1 and GM-CSF were proposed to be the optimal potential targets to improve chemotherapeutic effects. In immunocompetent murine models, we demonstrated that combined blockade of TGF-β1 and GM-CSF improved the chemotherapeutic effects by inhibition of M2-polarized TAM and induction of CD8 positive T cells. This study presents a novel promising combined strategy to improve the chemotherapeutic effects for pancreatic cancer.