Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy.
Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy.
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抑制CCL2受体CCR2可增强肿瘤对免疫检查点治疗的反应。
DOI：
10.1038/s42003-020-01441-y
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发表时间：
2020-11-27
影响因子：
5.9
通讯作者：
Theodorescu D
中科院分区：
文献类型：
--
作者：
Tu MM;Abdel-Hafiz HA;Jones RT;Jean A;Hoff KJ;Duex JE;Chauca-Diaz A;Costello JC;Dancik GM;Tamburini BAJ;Czerniak B;Kaye J;Theodorescu D
靶向PD-1/PD-L1轴的免疫疗法现在是多种癌症类型的临床管理的支柱，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，并且已被证明与不良预后相关。因此，抑制或阻断CCL2/CCR2信号传导轴已成为癌症治疗的关注领域。在这里，我们在多种鼠肿瘤和转移模型中显示，与抗PD-1单药治疗相比，CCR2拮抗作用与抗PD-1治疗组合导致致敏和增强的肿瘤应答。我们发现，增强的治疗反应与增强的CD8 + T细胞募集和活化以及伴随的CD4+调节性T细胞减少相关。这些结果为在多种肿瘤类型中将CCR2拮抗作用与PD-1/PD-L1导向的免疫疗法相结合的进一步临床探索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。Tu et al研究了细胞因子CCL2作为治疗靶点诱导的信号传导，证明了CCL2受体CCR2的阻断可增强CD8 + T细胞的募集和活化以及PD-1抑制在肿瘤中的治疗功效。
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. Investigating signalling induced by the cytokine CCL2 as a therapeutic target, Tu et al demonstrate that blockade of the CCL2 receptor, CCR2 enhances CD8+ T cell recruitment and activation and the therapeutic efficacy of PD-1 inhibition in tumours.
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影响因子：
2
作者：
Dancik GM
通讯作者：
Dancik GM
影响因子：
11.2
作者：
Fridlender ZG;Buchlis G;Kapoor V;Cheng G;Sun J;Singhal S;Crisanti MC;Wang LC;Heitjan D;Snyder LA;Albelda SM
通讯作者：
Albelda SM
DOI：
10.1007/978-1-4939-8570-8_3
发表时间：
2018
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Gibbings SL;Jakubzick CV
通讯作者：
Jakubzick CV
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1097/01.asn.0000089563.63641.a8
发表时间：
2003-10-01
影响因子：
13.6
作者：
Furuichi, K;Wada, T;Yokoyama, H
通讯作者：
Yokoyama, H