Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.
Cancer-Associated Fibroblasts Neutralize the Anti-tumor Effect of CSF1 Receptor Blockade by Inducing PMN-MDSC Infiltration of Tumors.
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DOI：
10.1016/j.ccell.2017.10.005
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发表时间：
2017-11-13
期刊：
影响因子：
50.3
通讯作者：
Gabrilovich DI
中科院分区：
文献类型：
--
作者：
Kumar V;Donthireddy L;Marvel D;Condamine T;Wang F;Lavilla-Alonso S;Hashimoto A;Vonteddu P;Behera R;Goins MA;Mulligan C;Nam B;Hockstein N;Denstman F;Shakamuri S;Speicher DW;Weeraratna AT;Chao T;Vonderheide RH;Languino LR;Ordentlich P;Liu Q;Xu X;Lo A;Puré E;Zhang C;Loboda A;Sepulveda MA;Snyder LA;Gabrilovich DI
肿瘤相关巨噬细胞（TAM）参与肿瘤进展的各个方面。使用CSF 1 R抑制剂靶向TAM在治疗上是有吸引力的，但具有非常有限的抗肿瘤作用。在这里，我们已经确定了限制CSF 1 R靶向治疗效果的机制。我们证明了癌相关成纤维细胞（CAF）是募集粒细胞到肿瘤的趋化因子的主要来源。肿瘤细胞产生的CSF 1导致HDAC 2介导的CAF中粒细胞特异性趋化因子表达下调，从而限制了这些细胞向肿瘤的迁移。用CSF 1 R抑制剂治疗破坏了这种相互作用，并引发了粒细胞向肿瘤募集的显著增加。CSF 1 R抑制剂与CXCR 2拮抗剂联合使用可阻断肿瘤的粒细胞浸润，显示出较强的抗肿瘤作用。Kumar等人表明，CSF 1 R抑制改变了癌症相关成纤维细胞的趋化因子分泌，这吸引了促肿瘤PMN-MDSC并导致疗效差。CSF 1 R和CXCR 2的组合抑制阻断MDSC募集并减少肿瘤生长，这通过添加抗PD-1进一步改善。
Tumor associated macrophages (TAM) contribute to all aspects of tumor progression. Use of CSF1R inhibitors to target TAM is therapeutically appealing, but has had very limited antitumor effects. Here, we have identified the mechanism that limited the effect of CSF1R targeted therapy. We demonstrated that carcinoma associated fibroblasts (CAF) are major sources of chemokines that recruit granulocytes to tumors. CSF1 produced by tumor cells caused HDAC2-mediated down-regulation of granulocyte-specific chemokine expression in CAF, which limited migration of these cells to tumors. Treatment with CSF1R inhibitors disrupted this cross talk and triggered a profound increase in granulocyte recruitment to tumors. Combining CSF1R inhibitor with a CXCR2 antagonist blocked granulocyte infiltration of tumors and showed strong anti-tumor effects. Kumar et al. show that CSF1R inhibition alters chemokine secretion by cancer associated fibroblasts, which attracts pro-tumor PMN-MDSCs and results in poor efficacy. Combined inhibition of CSF1R and CXCR2 blocks MDSC recruitment and reduces tumor growth, which is further improved by the addition of anti-PD-1.
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影响因子：
10.1
作者：
Gabrilovich DI
通讯作者：
Gabrilovich DI
影响因子：
7.2
作者：
Coussens, Lisa M.;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.
DOI：
10.1073/pnas.1320318110
发表时间：
2013-12-10
影响因子：
11.1
作者：
Feig, Christine;Jones, James O.;Fearon, Douglas T.
通讯作者：
Fearon, Douglas T.
影响因子：
3.1
作者：
Guleria, I;Pollard, JW
通讯作者：
Pollard, JW
DOI：
10.1073/pnas.92.8.3439
发表时间：
1995-04-11
影响因子：
11.1
作者：
GREENBERG, NM;DEMAYO, F;ROSEN, JM
通讯作者：
ROSEN, JM