中山大学:靶向DKK1或可增强PD-1单抗在结直肠癌中的疗效
创作:aluba 审核:aluba 2021年04月05日
  • 在80名dMMR结直肠癌患者中,肿瘤组织中的DKK1表达上调与CD8+ T细胞浸润减少及肿瘤复发相关;
  • 在43名接受PD-1单抗治疗的dMMR结直肠癌患者中,高水平的血清DKK1与对PD-1单抗的较差应答相关;
  • 在CT26结直肠癌细胞系中,敲低或中和DKK1可增加CD8+ T细胞的细胞毒性;
  • DKK1可降低CD8+ T细胞的T-bet表达并激活GSK3β;
  • 在dMMR结直肠癌类器官中,PD-1单抗或DKK1单抗均可增加凋亡细胞的比例,且同时中和PD-1及DKK1具有协同作用。
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aluba
Dickkopf 1(DKK1)与肿瘤进展相关。来自中山大学的丁培荣团队在Journal for ImmunoTherapy of Cancer上发表的一项最新研究,在错配修复缺陷(dMMR)结直肠癌患者中发现,肿瘤组织中的DKK1表达增加与复发及CD8+ T细胞的浸润减少相关,而血清DKK1表达增加与较差的PD-1单抗治疗效果相关。该研究结果提示,靶向DKK1或可恢复结直肠癌患者对PD-1单抗的应答。
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Dickkopf 1 impairs the tumor response to PD-1 blockade by inactivating CD8+ T cells in deficient mismatch repair colorectal cancer

在错配修复缺陷结直肠癌中,Dickkopf 1通过使CD8+ T细胞失活以抑制对PD-1阻断的肿瘤应答

10.1136/jitc-2020-001498

2021-03-29, Article

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Background: Dickkopf 1 (DKK1) is associated with tumor progression. However, whether DKK1 influences the tumor response to programmed cell death protein 1 (PD-1) blockade in colorectal cancers (CRCs) with deficient mismatch repair (dMMR) or microsatellite instability (MSI) has never been clarified.
Methods: Tumor tissues from 80 patients with dMMR CRC were evaluated for DKK1 expression and immune status via immunohistochemistry. Serum DKK1 was measured in another set of 43 patients who received PD-1 blockade therapy. CT26 cells and dMMR CRC organoids were cocultured with T cells, and CT26-grafted BALB/c mice were also constructed. T-cell cytotoxicity was assessed by apoptosis assays and flow cytometry. The pathway through which DKK1 regulates CD8+ T cells was investigated using RNA sequencing, and chromatin immunoprecipitation and luciferase reporter assays were conducted to determine the downstream transcription factors of DKK1.
Results: Elevated DKK1 expression was associated with recurrence and decreased CD8+ T-cell infiltration in dMMR CRCs, and patients with high-serum DKK1 had a poor response to PD-1 blockade. RNA interference or neutralization of DKK1 in CRC cells enhanced CD8+ T-cell cytotoxicity, while DKK1 decreased T-bet expression and activated GSK3β in CD8+ T cells. In addition, E2F1, a downstream transcription factor of GSK3β, directly upregulated T-bet expression. In organoid models, the proportion of apoptotic cells was elevated after individual neutralization of PD-1 or DKK1 and was further increased on combined neutralization of PD-1 and DKK1.
Conclusions: DKK1 suppressed the antitumor immune reaction through the GSK3β/E2F1/T-bet axis in CD8+ T cells. Elevated serum DKK1 predicted poor tumor response to PD-1 blockade in dMMR/MSI CRCs, and DKK1 neutralization may restore sensitivity to PD-1 blockade.

First Authors:
Qiaoqi Sui

Correspondence Authors:
Pei-Rong Ding

All Authors:
Qiaoqi Sui,Dingxin Liu,Wu Jiang,Jinghua Tang,Lingheng Kong,Kai Han,Leen Liao,Yuan Li,Qingjian Ou,Binyi Xiao,Guochen Liu,Yihong Ling,Jiewei Chen,Zexian Liu,Zhixiang Zuo,Zhizhong Pan,Penghui Zhou,Jian Zheng,Pei-Rong Ding

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