Maraviroc decreases CCL8-mediated migration of CCR5+ regulatory T cells and reduces metastatic tumor growth in the lungs
Maraviroc decreases CCL8-mediated migration of CCR5+ regulatory T cells and reduces metastatic tumor growth in the lungs
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DOI：
10.1080/2162402x.2016.1150398
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发表时间：
2016-01-01
期刊：
影响因子：
7.2
通讯作者：
Bennewith, K. L.
中科院分区：
文献类型：
--
作者：
Halvorsen, E. C.;Hamilton, M. J.;Bennewith, K. L.
调节性T细胞（TCRs）在免疫稳态调节中起着至关重要的生理作用，尽管最近的数据表明TCRs可以通过抑制抗肿瘤免疫应答来促进原发性肿瘤的生长。虽然关于转移性靶器官中的TcB表型和功能的信息很少，但TcB也可能影响肿瘤转移的发展。在此，我们证明原位植入的转移性乳腺肿瘤诱导肺中显著的Treg积累，肺是乳腺肿瘤转移的部位。相对于无肿瘤小鼠的乳腺脂肪垫和肺中的TCR 4，原发性肿瘤和转移性肺中的TCR 4表达高水平的C-C趋化因子受体5型（CCR 5），并且与其他免疫细胞群体相比，转移性肺中的TCR 4富集CCR 5表达。我们还鉴定了C-C趋化因子配体8（CCL 8），CCR 5的内源性配体，由患有转移性原发性肿瘤的小鼠肺中的F4/80（+）巨噬细胞产生。在CCR 5抑制剂马拉韦罗的存在下，Tcl 3向CCL 8的离体迁移减少。重要的是，用Maraviroc（MVC）治疗小鼠可降低CCR 5（+）T细胞水平和肺中的转移性肿瘤负荷。这项工作提供了CCL 8/CCR 5信号传导轴驱动Treg募集到携带转移性原发性肿瘤的小鼠的肺部的证据，代表了减少Treg积累和转移性肿瘤生长的潜在治疗靶点。
Regulatory T cells (Tregs) play a crucial physiological role in the regulation of immune homeostasis, although recent data suggest Tregs can contribute to primary tumor growth by suppressing antitumor immune responses. Tregs may also influence the development of tumor metastases, although there is a paucity of information regarding the phenotype and function of Tregs in metastatic target organs. Herein, we demonstrate that orthotopically implanted metastatic mammary tumors induce significant Treg accumulation in the lungs, which is a site of mammary tumor metastasis. Tregs in the primary tumor and metastatic lungs express high levels of C-C chemokine receptor type 5 (CCR5) relative to Tregs in the mammary fat pad and lungs of tumor-free mice, and Tregs in the metastatic lungs are enriched for CCR5 expression in comparison to other immune cell populations. We also identify that C-C chemokine ligand 8 (CCL8), an endogenous ligand of CCR5, is produced by F4/80(+) macrophages in the lungs of mice with metastatic primary tumors. Migration of Tregs toward CCL8 ex vivo is reduced in the presence of the CCR5 inhibitor Maraviroc. Importantly, treatment of mice with Maraviroc (MVC) reduces the level of CCR5(+) Tregs and metastatic tumor burden in the lungs. This work provides evidence of a CCL8/CCR5 signaling axis driving Treg recruitment to the lungs of mice bearing metastatic primary tumors, representing a potential therapeutic target to decrease Treg accumulation and metastatic tumor growth.