Targeting of colony-stimulating factor 1 receptor (CSF1R) in the CLL microenvironment yields antineoplastic activity in primary patient samples.
Targeting of colony-stimulating factor 1 receptor (CSF1R) in the CLL microenvironment yields antineoplastic activity in primary patient samples.
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DOI：
10.18632/oncotarget.25191
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发表时间：
2018-05-15
期刊：
影响因子：
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通讯作者：
Loriaux MM
中科院分区：
文献类型：
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作者：
Edwards V DK;Sweeney DT;Ho H;Eide CA;Rofelty A;Agarwal A;Liu SQ;Danilov AV;Lee P;Chantry D;McWeeney SK;Druker BJ;Tyner JW;Spurgeon SE;Loriaux MM
在许多恶性肿瘤中，肿瘤微环境包括表达 CSF1R 的支持性单核细胞/巨噬细胞，可促进肿瘤细胞存活。对于慢性淋巴细胞白血病 (CLL)，这些支持性单核细胞/巨噬细胞被称为护士样细胞 (NLC)，尽管 CSF1R 选择性小分子抑制剂对抗 CLL 的潜在有效性尚未得到充分研究。在这里，我们展示了两种 CSF1R 抑制剂 GW-2580 和 ARRY-382 在原发性 CLL 患者样本中的临床前活性。我们观察到至少 25% 的 CLL 样本对 CSF1R 抑制剂表现出亚微摩尔敏感性。在具有不同遗传和临床背景的样本中观察到这种敏感性，尽管较高的白细胞计数和单核细胞百分比与敏感性增加相关。耗尽表达 CD14 的单核细胞会优先降低对 CSF1R 抑制剂敏感的样品中的活力，而用 CSF1R 抑制剂处理样品会消除长期培养条件下 NLC 的存在。这些结果表明，CSF1R 小分子抑制剂靶向 CLL 微环境中表达 CD14 的单核细胞，从而剥夺白血病细胞的外在支持信号。此外，观察到 CSF1R 抑制剂与 idelalisib 或 ibrutinib（两种当前的 CLL 疗法，可破坏肿瘤细胞内在 B 细胞受体信号传导）相结合的显着协同作用。这些发现支持同时靶向支持性 NLC 和 CLL 细胞的概念，并证明了这种组合的潜在临床效用。
In many malignancies, the tumor microenvironment includes CSF1R-expressing supportive monocyte/macrophages that promote tumor cell survival. For chronic lymphocytic leukemia (CLL), these supportive monocyte/macrophages are known as nurse-like cells (NLCs), although the potential effectiveness of selective small-molecule inhibitors of CSF1R against CLL is understudied. Here, we demonstrate the preclinical activity of two inhibitors of CSF1R, GW-2580 and ARRY-382, in primary CLL patient samples. We observed at least 25% of CLL samples showed sub-micromolar sensitivity to CSF1R inhibitors. This sensitivity was observed in samples with varying genetic and clinical backgrounds, although higher white cell count and monocyte cell percentage was associated with increased sensitivity. Depleting CD14-expressing monocytes preferentially decreased viability in samples sensitive to CSF1R inhibitors, and treating samples with CSF1R inhibitors eliminated the presence of NLCs in long-term culture conditions. These results indicate that CSF1R small-molecule inhibitors target CD14-expressing monocytes in the CLL microenvironment, thereby depriving leukemia cells of extrinsic support signals. In addition, significant synergy was observed combining CSF1R inhibitors with idelalisib or ibrutinib, two current CLL therapies that disrupt tumor cell intrinsic B-cell receptor signaling. These findings support the concept of simultaneously targeting supportive NLCs and CLL cells and demonstrate the potential clinical utility of this combination.