ROS1 Fusion Mediates Immunogenicity by Upregulation of PD-L1 After the Activation of ROS1-SHP2 Signaling Pathway in Non-Small Cell Lung Cancer.
ROS1 Fusion Mediates Immunogenicity by Upregulation of PD-L1 After the Activation of ROS1-SHP2 Signaling Pathway in Non-Small Cell Lung Cancer.
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非小细胞肺癌中 ROS1-SHP2 信号通路激活后，ROS1 融合通过上调 PD-L1 介导免疫原性
DOI：
10.3389/fimmu.2020.527750
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发表时间：
2020
影响因子：
7.3
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Cai L;Duan J;Qian L;Wang Z;Wang S;Li S;Wang C;Zhao J;Zhang X;Bai H;Wang J
克唑替尼一线治疗ROS原癌基因1、受体酪氨酸激酶（ROS 1）融合的非小细胞肺癌（NSCLC）耐药是不可避免的。免疫检查点抑制剂（ICI）治疗是否适用于ROS 1融合NSCLC或在克唑替尼耐药发生后使用仍不清楚。在本研究中，培养了来自原代敏感HCC 78细胞的5种不同克唑替尼耐药浓度的细胞系（HCC 78 CR 1 -5）。使用表达克唑替尼敏感的ROS 1融合和克唑替尼耐药的ROS 1-G2032 R突变的Ba/F3细胞，探索ROS 1融合、ROS 1-G2032 R突变和程序性死亡配体1（PD-L1）表达之间的关系以及抗PD-L1 ICI治疗的临床潜力。利用RNA测序比较HCC 78和HCC 78 CR 1 -5细胞之间的信号通路网络。在具有Ba/F3 R 0 S1融合或R 0 S1-G2032 R突变的小鼠异种移植物模型上进行抗PD-L1 ICI治疗。HCC 78 CR 1 -5在免疫相关通路中表现出比HCC 78更强的免疫原性。ROS 1融合蛋白表达上调的HCC 78 CR 1 -5细胞PD-L1表达水平明显高于HCC 78原代细胞。此外，ROS 1 siRNA干扰可下调PD-L1的表达，而Ba/F3 ROS 1-G2032 R耐药突变体的PD-L1表达上调幅度低于ROS 1融合体。Western blotting分析显示，ROS 1-SHP 2信号通路在HCC 78 CR 1 -5细胞、Ba/F3细胞、ROS 1融合细胞和ROS 1-G2032 R抗性突变细胞中激活。在抗PD-L1治疗后，具有Ba/F3 ROS 1融合的小鼠异种移植模型在血液和组织中均显示出更多的CD 3 +PD-1+ T细胞，并且比具有Ba/F3 ROS 1-G2032 R抗性突变的细胞更敏感。我们的研究结果表明，PD-L1上调依赖于ROS 1融合超过ROS 1-G2032 R突变。我们分享了我们对非小细胞肺癌治疗管理的见解，即抗PD-L1 ICI疗法在ROS 1融合中的使用，而不是在ROS 1-G2032 R耐药突变中的使用。
The drug resistance of first-line crizotinib therapy for ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) fusion non-small cell lung cancer (NSCLC) is inevitable. Whether the administration of immune checkpoint inhibitor (ICI) therapy is suitable for ROS 1 fusion NSCLCs or after the development of crizotinib resistance is still unknown. In this study, five different crizotinib resistant concentration cell lines (HCC78CR1-5) from primary sensitive HCC78 cells were cultured. Ba/F3 cells expressing crizotinib sensitive ROS1 fusion and crizotinib resistant ROS1-G2032R mutation were used to explore the relationship between ROS1 fusion, ROS1-G2032R mutation and programmed death-ligand 1 (PD-L1) expression and the clinical potential of anti-PD-L1 ICI therapy. The signaling pathway net was compared between HCC78 and HCC78CR1-5 cells using RNA sequencing. Anti- PD-L1 ICI therapy was performed on mouse xenograft models with Ba/F3 ROS1 fusion or ROS1-G2032R mutation. HCC78CR1-5 showed more immunogenicity than HCC78 in immune-related pathways. The PD-L1 expression level was remarkably higher in HCC78CR1-5 with ROS1 fusion upregulation than HCC78 primary cell. Furthermore, the expression of PD-L1 was down-regulated by RNA interference with ROS1 siRNAs and up-regulated lower in Ba/F3 ROS1-G2032R resistant mutation than ROS1 fusion. Western blotting analysis showed the ROS1–SHP2 signaling pathway activation in HCC78CR1-5 cells, Ba/F3 ROS1 fusion and ROS1-G2032R resistant mutation. Mouse xenograft models with Ba/F3 ROS1 fusion showed more CD3+PD-1+ T cells both in blood and tissue, and more sensitivity than the cells with Ba/F3 ROS1-G2032R resistant mutation after anti-PD-L1 therapy. Our findings indicate that PD-L1 upregulation depends on ROS1 fusion more than ROS1-G2032R mutation. We share our insights of NSCLCs treatment management into the use of anti-PD-L1 ICI therapy in ROS1 fusion and not in ROS1-G2032R resistant mutation.
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影响因子：
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