Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy
Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy
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DOI：
10.1182/blood-2009-08-237412
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发表时间：
2010-02-18
期刊：
影响因子：
20.3
通讯作者：
Wu, Lily
中科院分区：
文献类型：
--
作者：
Priceman, Saul J.;Sung, James L.;Wu, Lily
肿瘤浸润性髓样细胞（TIM）通过促进血管生成和抑制抗肿瘤免疫应答来支持肿瘤生长。CSF-1受体（CSF 1 R）信号传导对于募集CD 11b（+）F4/80（+）肿瘤相关巨噬细胞（TAM）非常重要，并有助于骨髓细胞介导的血管生成。然而，CSF 1 R信号通路对其他TIM亚群（包括CD 11b（+）Gr-1（+）髓源性抑制细胞（MDSC））的影响尚不清楚。肿瘤浸润性MDSC也被证明有助于肿瘤血管生成，最近被认为与肿瘤对抗血管生成治疗的耐药性有关，但它们在这些过程中的确切参与还没有很好的了解。在这里，我们使用CSF 1 R信号传导的选择性药理学抑制剂GW 2580来证明CSF-1调节CD 11b（+）Gr-1（lo）Ly 6（Chi）单核MDSC的肿瘤募集。靶向这些TIM子集可抑制与促血管生成和免疫抑制基因表达减少相关的肿瘤血管生成。使用GW 2580与抗VEGFR-2抗体的联合治疗协同抑制肿瘤生长并严重损害肿瘤血管生成，沿着逆转至少一种涉及MMP-9的TIM介导的抗血管生成代偿机制。这些数据突出了CSF 1 R信号传导在不同TIM亚群（包括MDSC）的募集和功能中的重要性，并验证了靶向CSF 1 R信号传导与抗血管生成药物联合治疗实体癌的益处。（血。2010; 115：1461-1471）
Tumor-infiltrating myeloid cells (TIMs) support tumor growth by promoting angiogenesis and suppressing antitumor immune responses. CSF-1 receptor (CSF1R) signaling is important for the recruitment of CD11b(+)F4/80(+) tumor-associated macrophages (TAMs) and contributes to myeloid cell-mediated angiogenesis. However, the impact of the CSF1R signaling pathway on other TIM subsets, including CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs), is unknown. Tumor-infiltrating MDSCs have also been shown to contribute to tumor angiogenesis and have recently been implicated in tumor resistance to antiangiogenic therapy, yet their precise involvement in these processes is not well understood. Here, we use the selective pharmacologic inhibitor of CSF1R signaling, GW2580, to demonstrate that CSF-1 regulates the tumor recruitment of CD11b(+)Gr-1(lo)Ly6(Chi) mononuclear MDSCs. Targeting these TIM subsets inhibits tumor angiogenesis associated with reduced expression of proangiogenic and immunosuppressive genes. Combination therapy using GW2580 with an anti-VEGFR-2 antibody synergistically suppresses tumor growth and severely impairs tumor angiogenesis along with reverting at least one TIM-mediated antiangiogenic compensatory mechanism involving MMP-9. These data highlight the importance of CSF1R signaling in the recruitment and function of distinct TIM subsets, including MDSCs, and validate the benefits of targeting CSF1R signaling in combination with antiangiogenic drugs for the treatment of solid cancers. (Blood. 2010; 115: 1461-1471)