Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions.
Myeloid cell reprogramming alleviates immunosuppression and promotes clearance of metastatic lesions.
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DOI：
10.3389/fonc.2022.1039993
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
抑制性骨髓细胞，包括单核细胞和中性粒细胞群，在转移级联中发挥着至关重要的作用，并且可以抑制细胞毒性 T 细胞的抗肿瘤功能。无货物聚合物纳米颗粒（NP）已被证明可以调节多种异常炎症病理中的先天免疫细胞反应。在这里，我们测试了这样的假设：在转移性三阴性乳腺癌的 4T1 小鼠模型中静脉注射无药纳米颗粒可以通过靶向转移进展的促肿瘤免疫细胞介质来减少原发转移部位肺部的转移定植。体内研究表明，NP 给药可重新编程肺部的免疫环境并减少肺转移。肺部单细胞 RNA 测序显示，静脉注射 NP 会改变骨髓细胞表型和功能，使细胞群偏向炎症、抗肿瘤表型，远离促肿瘤表型。经 NP 处理的小鼠肺部的单核细胞、中性粒细胞和树突状细胞上调与 IFN 信号传导、TNF 信号传导和抗原呈递相关的基因通路。在 T 细胞缺陷模型中，NP 给药未能消除肺转移，这表明 T 细胞在 NP 介导的转移减少中发挥着重要作用。在手术切除原发肿瘤后，纳米颗粒作为辅助治疗，导致所有治疗小鼠体内已形成的肺转移灶被清除。总的来说，这些结果表明，体内施用无货物纳米粒子可以重新编程肺部的骨髓细胞反应，并以依赖于功能性 T 细胞的作用方法促进肺转移瘤的清除。
Suppressive myeloid cells, including monocyte and neutrophil populations, play a vital role in the metastatic cascade and can inhibit the anti-tumor function of cytotoxic T-cells. Cargo-free polymeric nanoparticles (NPs) have been shown to modulate innate immune cell responses in multiple pathologies of aberrant inflammation. Here, we test the hypothesis that the intravenous administration of drug-free NPs in the 4T1 murine model of metastatic triple-negative breast cancer can reduce metastatic colonization of the lungs, the primary metastatic site, by targeting the pro-tumor immune cell mediators of metastatic progression. In vivo studies demonstrated that NP administration reprograms the immune milieu of the lungs and reduces pulmonary metastases. Single-cell RNA sequencing of the lungs revealed that intravenous NP administration alters myeloid cell phenotype and function, skewing populations toward inflammatory, anti-tumor phenotypes and away from pro-tumor phenotypes. Monocytes, neutrophils, and dendritic cells in the lungs of NP-treated mice upregulate gene pathways associated with IFN signaling, TNF signaling, and antigen presentation. In a T-cell deficient model, NP administration failed to abrogate pulmonary metastases, implicating the vital role of T-cells in the NP-mediated reduction of metastases. NPs delivered as an adjuvant therapy, following surgical resection of the primary tumor, led to clearance of established pulmonary metastases in all treated mice. Collectively, these results demonstrate that the in vivo administration of cargo-free NPs reprograms myeloid cell responses at the lungs and promotes the clearance of pulmonary metastases in a method of action dependent on functional T-cells.
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影响因子：
6.4
作者：
Rotondo, Rita;Barisione, Gaia;Barbieri, Ottavia
通讯作者：
Barbieri, Ottavia
影响因子：
50.3
作者：
Granot Z;Henke E;Comen EA;King TA;Norton L;Benezra R
通讯作者：
Benezra R
影响因子：
17.4
作者：
Gustafson HH;Holt-Casper D;Grainger DW;Ghandehari H
通讯作者：
Ghandehari H
影响因子：
5.8
作者：
Allen, Riley P.;Bolandparvaz, Amir;Lewis, Jamal S.
通讯作者：
Lewis, Jamal S.
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影响因子：
15.8
作者：
Ali HR;Chlon L;Pharoah PD;Markowetz F;Caldas C
通讯作者：
Caldas C