Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.
Leukocyte complexity predicts breast cancer survival and functionally regulates response to chemotherapy.
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DOI：
10.1158/2159-8274.cd-10-0028
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发表时间：
2011-06
期刊：
影响因子：
28.2
通讯作者：
Coussens LM
中科院分区：
文献类型：
--
作者：
DeNardo DG;Brennan DJ;Rexhepaj E;Ruffell B;Shiao SL;Madden SF;Gallagher WM;Wadhwani N;Keil SD;Junaid SA;Rugo HS;Hwang ES;Jirström K;West BL;Coussens LM
免疫调节途径影响癌症发展的多个方面。在这篇文章中，我们证明了乳腺癌中巨噬细胞丰度和T细胞丰度都是无复发和总生存率的预后指标。我们提供的证据表明，对化疗的反应部分由这些白细胞调节;细胞毒性疗法诱导乳腺上皮细胞产生单核细胞/巨噬细胞募集因子，包括集落刺激因子1（CSF 1）和白细胞介素-34，它们共同增强CSF 1受体（CSF 1 R）依赖性巨噬细胞浸润。用CSF 1 R信号传导拮抗剂阻断巨噬细胞募集，与紫杉醇联合，通过减缓原发性肿瘤的发展和减少肺转移来改善乳腺肿瘤荷瘤小鼠的存活率。乳腺癌发生的这些改善方面伴随着血管密度降低和以CD 8 + T细胞依赖性方式促进肿瘤抑制的抗肿瘤免疫程序的出现。这些数据为靶向巨噬细胞募集/反应途径（特别是CSF 1 R）与细胞毒性治疗联合提供了依据，并确定了可能从这种新型治疗方法中获益的乳腺癌人群。
Immune-regulated pathways influence multiple aspects of cancer development. In this article we demonstrate that both macrophage abundance and T-cell abundance in breast cancer represent prognostic indicators for recurrence-free and overall survival. We provide evidence that response to chemotherapy is in part regulated by these leukocytes; cytotoxic therapies induce mammary epithelial cells to produce monocyte/macrophage recruitment factors, including colony stimulating factor 1 (CSF1) and interleukin-34, which together enhance CSF1 receptor (CSF1R)–dependent macrophage infiltration. Blockade of macrophage recruitment with CSF1R-signaling antagonists, in combination with paclitaxel, improved survival of mammary tumor–bearing mice by slowing primary tumor development and reducing pulmonary metastasis. These improved aspects of mammary carcinogenesis were accompanied by decreased vessel density and appearance of antitumor immune programs fostering tumor suppression in a CD8+ T-cell–dependent manner. These data provide a rationale for targeting macrophage recruitment/ response pathways, notably CSF1R, in combination with cytotoxic therapy, and identification of a breast cancer population likely to benefit from this novel therapeutic approach.