Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1β in tumor-associated macrophages.
Mammary tumor-derived CCL2 enhances pro-metastatic systemic inflammation through upregulation of IL1β in tumor-associated macrophages.
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DOI：
10.1080/2162402x.2017.1334744
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发表时间：
2017
期刊：
影响因子：
7.2
通讯作者：
de Visser KE
中科院分区：
文献类型：
--
作者：
Kersten K;Coffelt SB;Hoogstraat M;Verstegen NJM;Vrijland K;Ciampricotti M;Doornebal CW;Hau CS;Wellenstein MD;Salvagno C;Doshi P;Lips EH;Wessels LFA;de Visser KE
患有原发性实体恶性肿瘤的患者经常表现出全身炎症的迹象。值得注意的是，在癌症患者中经常观察到中性粒细胞及其相关可溶性介质水平升高，并且与生存率降低和转移形成增加相关。最近，我们在侵袭性乳腺癌基因工程小鼠模型中证明了乳腺肿瘤诱导的产生 IL17 的 γδ T 细胞、免疫抑制性中性粒细胞的系统性扩张和转移形成之间的机制联系。肿瘤如何协调这种全身炎症级联以促进传播仍不清楚。在这里，我们表明该级联的激活依赖于 CCL2 介导的肿瘤相关巨噬细胞中 IL1β 的诱导。与这些发现一致，人类乳腺肿瘤中 CCL2 的表达与 IL1β 和巨噬细胞标记物呈正相关。我们证明，在患有乳腺肿瘤的小鼠中阻断 CCL2 会导致 γδ T 细胞产生 IL17 减少、中性粒细胞扩增减少并增强 CD8+ T 细胞活性。这些结果凸显了 CCL2 在促进乳腺癌诱导的促转移性全身炎症 γδ T 细胞 - IL17 - 中性粒细胞轴方面的新作用。
Patients with primary solid malignancies frequently exhibit signs of systemic inflammation. Notably, elevated levels of neutrophils and their associated soluble mediators are regularly observed in cancer patients, and correlate with reduced survival and increased metastasis formation. Recently, we demonstrated a mechanistic link between mammary tumor-induced IL17-producing γδ T cells, systemic expansion of immunosuppressive neutrophils and metastasis formation in a genetically engineered mouse model for invasive breast cancer. How tumors orchestrate this systemic inflammatory cascade to facilitate dissemination remains unclear. Here we show that activation of this cascade relies on CCL2-mediated induction of IL1β in tumor-associated macrophages. In line with these findings, expression of CCL2 positively correlates with IL1Β and macrophage markers in human breast tumors. We demonstrate that blockade of CCL2 in mammary tumor-bearing mice results in reduced IL17 production by γδ T cells, decreased neutrophil expansion and enhanced CD8+ T cell activity. These results highlight a new role for CCL2 in facilitating the breast cancer-induced pro-metastatic systemic inflammatory γδ T cell – IL17 – neutrophil axis.