Inhibition of DCLK1 kinase reverses epithelial-mesenchymal transition and restores T-cell activity in pancreatic ductal adenocarcinoma.
Inhibition of DCLK1 kinase reverses epithelial-mesenchymal transition and restores T-cell activity in pancreatic ductal adenocarcinoma.
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抑制 DCLK1 激酶可逆转胰腺导管腺癌的上皮间质转化并恢复 T 细胞活性
DOI：
10.1016/j.tranon.2021.101317
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发表时间：
2022-03
影响因子：
5
通讯作者：
An G
中科院分区：
文献类型：
--
作者：
Ge Y;Liu H;Zhang Y;Liu J;Yan R;Xiao Z;Fan X;Huang X;An G
DCLK1 长亚型 (DCLK1-iso1) 和短亚型 (DCLK1-iso4) 均促进胰腺癌细胞中的上皮-间质转化。免疫抑制成分在“间充质”胰腺癌中高度丰富。在 DCLK1 过表达的肿瘤中，CD4 和 CD8+ T 细胞的浸润减少，而 M2 巨噬细胞增加。 DCLK1 抑制剂可以逆转 EMT 程序并恢复 T 细胞活性。免疫疗法最近已成为一种有前途的癌症疗法，广泛应用免疫检查点抑制剂（ICIs）。然而，由于免疫抑制微环境，胰腺导管腺癌（PDAC）似乎对免疫治疗没有反应。近期研究表明肿瘤干细胞标志物DCLK1促进PDAC的发生和发展。然而，驱动这一过程的机制仍不清楚。在这里，通过在 PDAC 细胞系中进行功能获得研究，我们证明 DCLK1 长亚型（DCLK1-iso1、DCLK1-AS）和短亚型（DCLK1-iso4、DCLK1-BL）都可以有效激活 EMT，从而导致肿瘤迁移和侵袭。与体外实验一致，生物信息学分析表明 DCLK1 可能充当 PDAC 中 EMT 激活的驱动因素。进一步分析表明，EMT与免疫抑制微环境有关，其中包括更多的免疫抑制细胞和趋化因子，根据TIDE（肿瘤免疫功能障碍和排除）算法，EMT评分较高的患者对免疫检查点抑制剂的敏感性较低。多重免疫荧光结果表明 PDAC 患者中 DCLK1、EMT 和免疫抑制之间存在密切相关性。这些发现在体内得到进一步证实，反映在 DCLK1 过表达的皮下肿瘤中 CD4+、CD8+ T 细胞减少、M2 巨噬细胞增加以及 E-cad 丢失。重要的是，高度特异性的 DCLK1 抑制剂 (DCLK1-IN-1) 能够有效阻断 EMT 过程并恢复 T 细胞活性。总而言之，我们的数据表明 DCLK1 与 PDAC 中的肿瘤免疫逃逸密切相关，抑制 DCLK1 激酶活性可能是一种有前途的治疗方式。
Both DCLK1 long (DCLK1-iso1) and short (DCLK1-iso4) isoforms promote epithelial-mesenchymal transition in pancreatic cancer cells. Immunosuppressive components are highly enriched in “mesenchymal” pancreatic cancer. The infiltration of CD4 and CD8+ T cells decrease while the M2 macrophages increase in DCLK1-overexpressing tumors. DCLK1 inhibitor could reverse EMT program and restore T-cells activity. Immunotherapy has recently become a promising cancer therapy with extensive applications of immune checkpoint inhibitors (ICIs). However, pancreatic ductal adenocarcinoma (PDAC) appears to be unresponsive to immunotherapy due to the immunosuppressive microenvironment. Recent studies showed that cancer stem cell marker DCLK1 promoted the initiation and development of PDAC. Nevertheless, the mechanism driving this process remains unclear. Here, by performing gain-of-function investigations in PDAC cell lines, we demonstrate that both DCLK1 long (DCLK1-iso1, DCLK1-AS) and short (DCLK1-iso4, DCLK1-BL) isoforms can efficiently activate EMT leading to tumor migration and invasion. Consistent with experiments in vitro, bioinformatic analysis demonstrates that DCLK1 may act as a driver of EMT activation in PDAC. Further analysis showed that EMT was associated with an immunosuppressive microenvironment, which includes more immunosuppressive cells and chemokines, and patients with a higher EMT score were less sensitive to immune checkpoint inhibitors according to the TIDE (Tumor Immune Dysfunction and Exclusion) algorithm. Multiplexed immunofluorescence results demonstrated the close correlation between DCLK1, EMT and immunosuppression in PDAC patients. The findings were further confirmed in vivo reflected by decreased CD4+, CD8+ T cells and increased M2 macrophages as well as E-cad loss in DCLK1-overexpressing subcutaneous tumors. Importantly, the highly-specific DCLK1 inhibitor (DCLK1-IN-1) was able to effectively block EMT process and restore T-cell activity. Altogether, our data demonstrate that DCLK1 is strongly associated with tumor immune escape in PDAC and inhibiting DCLK1 kinase activity may be a promising therapeutic modality.
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影响因子：
--
作者：
Liu, Heshu;Wen, Tao;An, Guangyu
通讯作者：
An, Guangyu
影响因子：
6.4
作者：
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通讯作者：
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影响因子：
1.3
作者：
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通讯作者：
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影响因子：
50.3
作者：
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通讯作者：
Yang, Muh-Hwa
DOI：
10.1158/1078-0432.ccr-15-1434
发表时间：
2016-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Lou Y;Diao L;Cuentas ER;Denning WL;Chen L;Fan YH;Byers LA;Wang J;Papadimitrakopoulou VA;Behrens C;Rodriguez JC;Hwu P;Wistuba II;Heymach JV;Gibbons DL
通讯作者：
Gibbons DL