Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer.
Tumour-infiltrating neutrophils counteract anti-VEGF therapy in metastatic colorectal cancer.
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DOI：
10.1038/s41416-018-0198-3
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发表时间：
2019-01
影响因子：
8.8
通讯作者：
Coutelle O
中科院分区：
文献类型：
--
作者：
Schiffmann LM;Fritsch M;Gebauer F;Günther SD;Stair NR;Seeger JM;Thangarajah F;Dieplinger G;Bludau M;Alakus H;Göbel H;Quaas A;Zander T;Hilberg F;Bruns CJ;Kashkar H;Coutelle O
免疫浸润与抗血管生成癌症治疗的获得性耐药性的发展有关。因此，我们研究了结直肠癌（CRC）患者转移中的中性粒细胞浸润与贝伐单抗治疗后生存率之间的相关性。我们的研究确定 CD177+ 肿瘤中性粒细胞浸润是贝伐珠单抗治疗的不良预后因素。我们进一步证明，一种新型抗 VEGF/抗 Ang2 化合物 (BI-880) 可以克服实验肿瘤模型中对 VEGF 抑制的耐药性。总共 85 名转移性 CRC 患者被分为单独接受化疗 (n = 39) 或联合贝伐珠单抗 (n = 46) 的队列。肿瘤 CD177+ 中性粒细胞浸润与临床结果相关。通过免疫组织化学在异种移植和同基因肿瘤模型中研究中性粒细胞浸润对抗 VEGF 或抗 VEGF/抗 Ang2 治疗的影响。与携带 CD177− 转移的患者相比，在存在 CD177+ 浸润的情况下接受贝伐珠单抗治疗的 CRC 患者的生存率显着降低。 BI-880 治疗减少了与贝伐单抗治疗相关的缺氧的发生，并改善了异种移植物的血管正常化。此外，中性粒细胞耗竭或 BI-880 治疗可恢复抗 VEGF 耐药性同基因肿瘤模型的治疗敏感性。我们的研究结果表明 CD177 作为贝伐珠单抗的生物标志物，并表明 VEGF/Ang2 抑制可作为克服中性粒细胞相关抗血管生成治疗耐药的策略。
Immune infiltration is implicated in the development of acquired resistance to anti-angiogenic cancer therapy. We therefore investigated the correlation between neutrophil infiltration in metastasis of colorectal cancer (CRC) patients and survival after treatment with bevacizumab. Our study identifies CD177+ tumour neutrophil infiltration as an adverse prognostic factor for bevacizumab treatment. We further demonstrate that a novel anti-VEGF/anti-Ang2 compound (BI-880) can overcome resistance to VEGF inhibition in experimental tumour models. A total of 85 metastatic CRC patients were stratified into cohorts that had either received chemotherapy alone (n = 39) or combined with bevacizumab (n = 46). Tumour CD177+ neutrophil infiltration was correlated to clinical outcome. The impact of neutrophil infiltration on anti-VEGF or anti-VEGF/anti-Ang2 therapy was studied in both xenograft and syngeneic tumour models by immunohistochemistry. The survival of bevacizumab-treated CRC patients in the presence of CD177+ infiltrates was significantly reduced compared to patients harbouring CD177− metastases. BI-880 treatment reduced the development of hypoxia associated with bevacizumab treatment and improved vascular normalisation in xenografts. Furthermore, neutrophil depletion or BI-880 treatment restored treatment sensitivity in a syngeneic tumour model of anti-VEGF resistance. Our findings implicate CD177 as a biomarker for bevacizumab and suggest VEGF/Ang2 inhibition as a strategy to overcome neutrophil associated resistance to anti-angiogenic treatment.
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结直肠癌瘤内中性粒细胞增多与恶性表型密切相关，可预测患者的不良预后。
影响因子：
3.7
作者：
Rao HL;Chen JW;Li M;Xiao YB;Fu J;Zeng YX;Cai MY;Xie D
通讯作者：
Xie D
影响因子：
8.8
作者：
Schiffmann LM;Brunold M;Liwschitz M;Goede V;Loges S;Wroblewski M;Quaas A;Alakus H;Stippel D;Bruns CJ;Hallek M;Kashkar H;Hacker UT;Coutelle O
通讯作者：
Coutelle O
影响因子：
3.8
作者：
Fujii T;Tabe Y;Yajima R;Yamaguchi S;Tsutsumi S;Asao T;Kuwano H
通讯作者：
Kuwano H
影响因子：
20.3
作者：
Bai, Ming;Grieshaber-Bouyer, Ricardo;Nigrovic, Peter A.
通讯作者：
Nigrovic, Peter A.
影响因子：
11.2
作者：
Hashizume H;Falcón BL;Kuroda T;Baluk P;Coxon A;Yu D;Bready JV;Oliner JD;McDonald DM
通讯作者：
McDonald DM