Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment.
Human prostate cancer bone metastases have an actionable immunosuppressive microenvironment.
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DOI：
10.1016/j.ccell.2021.09.005
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发表时间：
2021-11-08
期刊：
影响因子：
50.3
通讯作者：
as part of the Boston Bone Metastases Consortium
中科院分区：
文献类型：
--
作者：
Kfoury Y;Baryawno N;Severe N;Mei S;Gustafsson K;Hirz T;Brouse T;Scadden EW;Igolkina AA;Kokkaliaris K;Choi BD;Barkas N;Randolph MA;Shin JH;Saylor PJ;Scadden DT;Sykes DB;Kharchenko PV;as part of the Boston Bone Metastases Consortium
骨转移是癌症的毁灭性并发症。它们在前列腺癌（PCa）中特别常见，代表不可治愈的疾病，并且对免疫疗法无效。我们试图通过分析来自骨转移性前列腺肿瘤、受累BM、未受累BM以及来自无癌骨科患者和健康个体的BM的单细胞来定义骨髓（BM）微环境的独特特征。转移性PCa与多方面的免疫畸变相关，特别是不同T细胞亚群的耗竭，具有PCa骨转移特异性状态的巨噬细胞的出现。趋化因子CCL 20被髓样细胞显著过表达，其在T细胞上的同源CCR 6受体也是如此。在具有同基因PCa骨转移的小鼠中，CCL 20-CCR 6轴的破坏恢复了T细胞反应性并显著降低了动物存活率。PCa骨转移的比较高分辨率分析显示了缓解局部免疫抑制以获得治疗效果的靶向方法。Kfoury等人，鉴定人骨转移性前列腺癌中的免疫抑制微环境，所述人骨转移性前列腺癌富含耗尽的T细胞并由过表达CCL 20的骨髓细胞协调。在动物模型中对CCL 20/CCR 6轴的药理学或遗传靶向缓解了免疫抑制状态并延长了携带转移性肿瘤的小鼠的存活期。
Bone metastases are devastating complications of cancer. They are particularly common in prostate cancer (PCa), represent incurable disease and are refractory to immunotherapy. We seek to define distinct features of the bone marrow (BM) microenvironment by analyzing single cells from bone metastatic prostate tumors, involved BM, uninvolved BM as well as BM from cancer-free, orthopedic patients and healthy individuals. Metastatic PCa is associated with multifaceted immune distortion, specifically exhaustion of distinct T cell subsets, appearance of macrophages with states specific to PCa bone metastases. The chemokine CCL20 is notably overexpressed by myeloid cells, as is its cognate CCR6 receptor on T cells. Disruption of the CCL20-CCR6 axis in mice with syngeneic PCa bone metastases restores T cell reactivity and significantly prolongs animal survival. Comparative high-resolution analysis of PCa bone metastases shows a targeted approach for relieving local immunosuppression for therapeutic effect. Kfoury et al., identify an immune-suppressive microenvironment in human bone metastatic prostate cancer enriched in exhausted T cells and orchestrated by myeloid cells overexpressing CCL20. Pharmacological or genetic targeting of the CCL20/CCR6 axes in an animal model relieves the immune-suppressive state and extends the survival of metastatic tumor bearing mice.
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影响因子：
8
作者：
Fergusson JR;Hühn MH;Swadling L;Walker LJ;Kurioka A;Llibre A;Bertoletti A;Holländer G;Newell EW;Davis MM;Sverremark-Ekström E;Powrie F;Capone S;Folgori A;Barnes E;Willberg CB;Ussher JE;Klenerman P
通讯作者：
Klenerman P
DOI：
10.1073/pnas.1704958114
发表时间：
2017-11-21
影响因子：
11.1
作者：
Getschman, A. E.;Imai, Y.;Volkman, B. F.
通讯作者：
Volkman, B. F.
影响因子：
48
作者：
Barkas, Nikolas;Petukhov, Viktor;Kharchenko, Peter V.
通讯作者：
Kharchenko, Peter V.
影响因子：
--
作者：
Ikeda S;Kitadate A;Ito M;Abe F;Nara M;Watanabe A;Takahashi N;Miyagaki T;Sugaya M;Tagawa H
通讯作者：
Tagawa H
影响因子：
14.8
作者：
Efremova, Mirjana;Vento-Tormo, Miquel;Vento-Tormo, Roser
通讯作者：
Vento-Tormo, Roser