CCR1 and CCR5 mediate cancer-induced myelopoiesis and differentiation of myeloid cells in the tumor.
CCR1 and CCR5 mediate cancer-induced myelopoiesis and differentiation of myeloid cells in the tumor.
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DOI：
10.1136/jitc-2021-003131
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发表时间：
2022-01
影响因子：
10.9
通讯作者：
Serafini P
中科院分区：
文献类型：
--
作者：
Zilio S;Bicciato S;Weed D;Serafini P
癌症诱导的“紧急”骨髓生成通过诱导具有抑制表型的髓样细胞在外周和肿瘤中的积累在肿瘤进展中起关键作用。趋化因子受体（CCR），特别是CCR 1、CCR 2、CCR 5和CCR 7正在成为骨髓细胞运输和功能的关键调节因子，但由于趋化因子的信号冗余、整合和混杂以及这些CCR在其他白细胞亚群上的表达，它们的确切作用尚未完全阐明。我们使用4PD纳米颗粒在荷瘤小鼠的骨髓细胞中体内靶向沉默CCR 1、CCR 2、CCR 5和/或CCR 7，以评估治疗对肿瘤生长、骨髓细胞运输和极化的影响。我们使用流式细胞术和图像细胞术以及功能测定来监测肿瘤微环境的变化，并通过耗竭实验和免疫缺陷小鼠来确定Ly 6 G+细胞在肿瘤进展过程中的作用。我们使用流式细胞术、转录组分析、细胞因子珠阵列、功能测定和CCR 1或CCR 5缺陷的小鼠进一步评估了趋化因子受体抑制和肿瘤衍生因子对小鼠和人造血干细胞和前体细胞（HSPC）的髓样细胞分化的影响。4PD介导的骨髓细胞和骨髓前体细胞上CCR 1和CCR 5的体内沉默是必要的，足以抑制肿瘤进展。功能研究表明，这种抗肿瘤作用不是通过改变髓系细胞的趋化因子介导的，而是通过多形核细胞髓系来源的抑制细胞（MDSC）复极化为肿瘤杀伤中性粒细胞。转录组功能和细胞因子分析表明，肿瘤衍生因子诱导HSPC中的CCL 3和CCL 4，通过CCR 1和CCR 5的自分泌参与，诱导HSPC在MDSC中分化。这些发现在具有不同遗传背景的小鼠中以及使用来自癌症患者的脐带血和外周血的HSPC得到证实。我们的数据支持CCR 1和CCR 5及其配体是由几种肿瘤衍生因子激活的主免疫枢纽的观点。该途径的激活对于MDSC和原瘤巨噬细胞的分化是必需的。
Cancer-induced ‘emergency’ myelopoiesis plays a key role in tumor progression by inducing the accumulation of myeloid cells with a suppressive phenotype peripherally and in the tumor. Chemokine receptors (CCRs) and, in particular, CCR1, CCR2, CCR5, and CCR7 are emerging as key regulators of myeloid cell trafficking and function but their precise role has not been completely clarified yet because of the signal redundancy, integration, and promiscuity of chemokines and of the expression of these CCRs on other leukocyte subsets. We used the 4PD nanoparticle for the in vivo targeted silencing of CCR1, CCR2, CCR5, and/or CCR7 in the myeloid cells of tumor bearing mice to evaluate the effect of treatments on tumor growth, myeloid cell trafficking and polarization. We used flow and image cytometry and functional assays to monitor changes in the tumor microenvironment and depletion experiments and immune deficient mice to determine the role of Ly6G+cells during tumor progression. We further evaluated in vitro the impact of chemokine receptor inhibition and tumor derived factors on myeloid cell differentiation from mouse and human hematopoietic stem and precursors cells (HSPCs) using flow cytometry, transcriptome analysis, cytokines beads arrays, functional assays, and mice deficient for CCR1 or CCR5. 4PD-mediated in vivo silencing of CCR1 and CCR5 on myeloid cells and myeloid precursors was necessary and sufficient to inhibit tumor progression. Functional studies indicated that this antitumor effect was not mediated by alteration of myeloid cell chemotaxes but rather by the repolarization of polymorphonuclear myeloid-derived suppressor cells (MDSCs) into tumoricidal neutrophils. Transcriptome functional and cytokine analysis indicated that tumor derived factors induced CCL3 and CCL4 in HSPCs that, through the autocrine engagement of CCR1 and CCR5, induced HSPCs differentiation in MDSCs. These finding were confirmed across mice with different genetic backgrounds and using HSPCs from umbilical cord blood and peripheral blood of patients with cancer. Our data support the notion that CCR1 and CCR5 and their ligands are a master immunological hub activated by several tumor derived factors. Activation of this pathway is necessary for the differentiation of MDSCs and protumoral macrophages.
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