当前位置: X-MOL 学术Commun. Biol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy
Communications Biology ( IF 5.9 ) Pub Date : 2020-11-27 , DOI: 10.1038/s42003-020-01441-y
Megan M Tu 1 , Hany A Abdel-Hafiz 2, 3 , Robert T Jones 4 , Annie Jean 4 , Katelyn J Hoff 5 , Jason E Duex 1 , Ana Chauca-Diaz 1 , James C Costello 4 , Garrett M Dancik 6 , Beth A Jirón Tamburini 5 , Bogdan Czerniak 7 , Jonathan Kaye 8 , Dan Theodorescu 3, 9
Affiliation  

Immunotherapies targeting the PD-1/PD-L1 axis are now a mainstay in the clinical management of multiple cancer types, however, many tumors still fail to respond. CCL2 is highly expressed in various cancer types and has been shown to be associated with poor prognosis. Inhibition or blockade of the CCL2/CCR2 signaling axis has thus been an area of interest for cancer therapy. Here we show across multiple murine tumor and metastasis models that CCR2 antagonism in combination with anti-PD-1 therapy leads to sensitization and enhanced tumor response over anti-PD-1 monotherapy. We show that enhanced treatment response correlates with enhanced CD8+ T cell recruitment and activation and a concomitant decrease in CD4+ regulatory T cell. These results provide strong preclinical rationale for further clinical exploration of combining CCR2 antagonism with PD-1/PD-L1-directed immunotherapies across multiple tumor types especially given the availability of small molecule CCR2 inhibitors and antibodies.



中文翻译:

抑制 CCL2 受体 CCR2 可增强肿瘤对免疫检查点治疗的反应

针对 PD-1/PD-L1 轴的免疫疗法现在是多种癌症类型临床管理的支柱,然而,许多肿瘤仍然没有反应。CCL2 在各种癌症类型中高度表达,并且已被证明与预后不良有关。因此,抑制或阻断 CCL2/CCR2 信号轴一直是癌症治疗的一个关注领域。在这里,我们在多个小鼠肿瘤和转移模型中显示,与抗 PD-1 单一疗法相比,CCR2 拮抗剂与抗 PD-1 疗法相结合导致致敏和增强的肿瘤反应。我们表明,增强的治疗反应与增强的 CD8 + T 细胞募集和激活以及伴随的 CD4 +减少相关调节性 T 细胞。这些结果为进一步临床探索在多种肿瘤类型中将 CCR2 拮抗剂与 PD-1/PD-L1 定向免疫疗法相结合提供了强有力的临床前依据,特别是考虑到小分子 CCR2 抑制剂和抗体的可用性。

更新日期:2020-11-27
down
wechat
bug