Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms
Immuno-subtyping of breast cancer reveals distinct myeloid cell profiles and immunotherapy resistance mechanisms
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DOI：
10.1038/s41556-019-0373-7
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发表时间：
2019-09-01
影响因子：
21.3
通讯作者：
Zhang, Xiang H-F
中科院分区：
文献类型：
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作者：
Kim, Ik Sun;Gao, Yang;Zhang, Xiang H-F
癌症诱导的免疫反应影响肿瘤的进展和治疗反应。在多个小鼠模型和临床数据集中，我们发现了中性粒细胞和巨噬细胞的大量变异，这些细胞定义了三阴性乳腺癌(TNBC)的免疫亚型，包括中性粒细胞富集型(NES)和巨噬细胞富集型(MES)。不同的肿瘤内在途径以及巨噬细胞(或单核细胞)和中性粒细胞之间的相互调节有助于二分髓系的发展。MES主要含有CCR2依赖的巨噬细胞，对免疫检查点阻断(ICB)表现出不同的反应。NES表现出全身性和局部性的免疫抑制中性粒细胞(或粒细胞髓系来源的抑制细胞)聚集，对ICB具有抵抗力，并含有少数似乎不受CCR2基因敲除影响的巨噬细胞。MES到NES的转换介导了最初敏感的MES模型的获得性ICB抗性。我们的结果显示了不同的髓系细胞频率、功能和在免疫治疗中的潜在作用，并强调了更好地了解患者间髓系间的异质性的必要性。
Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that define 'immune subtypes' of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells), is resistant to ICB, and contains a minority of macrophages that seem to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment.