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骨髓细胞通过 BCC-Ex 下调 CXCR4 的表达并激活 STAT3 信号通路分化为 MDSCs。

Bone marrow cells are differentiated into MDSCs by BCC-Ex through down-regulating the expression of CXCR4 and activating STAT3 signalling pathway.

机构信息

The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang, China.

School of Chemistry, Biology and Material Science, East China University of Technology, Nanchang, China.

出版信息

J Cell Mol Med. 2021 Jun;25(12):5497-5510. doi: 10.1111/jcmm.16559. Epub 2021 May 6.

DOI:10.1111/jcmm.16559
PMID:33955151
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8184685/
Abstract

Studies showed that the increase of myeloid-derived suppressor cells (MDSCs) in tumour microenvironment is closely related to the resistant treatment and poor prognosis of metastatic breast cancer. However, the effect of tumour-derived exosomes on MDSCs and its mechanism are not clear. Here, we reported that breast cancer cells (4T1)-secreted exosomes (BCC-Ex) were able to differentiate bone marrow cells into MDSCs and significantly inhibited the proliferation of T lymphocytes to provide an immunosuppressive microenvironment for cancer cells in vivo and in vitro. The number of MDSCs in bone marrow and spleen of 4T1 tumour-bearing mice and BCC-Ex infused mice was significantly higher than that of normal mice, whereas the number of T lymphocytes in spleen was significantly decreased. In addition, BCC-Ex markedly promoted the differentiation of MDSCs from bone marrow cells or bone marrow cells derived macrophages, seen as the increased expressions of MDSCs-related functional proteins Arginase-1 (Arg-1) and inducible nitric oxide synthase (iNOS). Furthermore, BCC-Ex significantly down-regulated the expressions of chemokine receptor CXCR4 and markedly up-regulated the levels of inflammatory cytokines IL-6 and IL-10 in bone marrow cells and macrophages and remarkably inhibited the division and proliferation of T cells. Importantly, CXCR4 agonist, CXCL12, could reverse the function of BCC-Ex, indicating that BCC-Ex-induced MDSCs might be dependent on the down-regulation of CXCR4. Western blot showed that BCC-Ex significantly promoted the phosphorylation of STAT3 in bone marrow cells, resulting in the inhibitions of the proliferation and apoptosis of bone marrow cells, and the aggravation of the differentiation of bone marrow cells into MDSCs.

摘要

研究表明，肿瘤微环境中髓系来源抑制细胞（MDSCs）的增加与转移性乳腺癌的耐药治疗和预后不良密切相关。然而，肿瘤来源的外泌体对 MDSCs 的影响及其机制尚不清楚。在这里，我们报道了乳腺癌细胞（4T1）分泌的外泌体（BCC-Ex）能够将骨髓细胞分化为 MDSCs，并显著抑制 T 淋巴细胞的增殖，从而在体内和体外为癌细胞提供免疫抑制微环境。4T1 荷瘤小鼠和 BCC-Ex 输注小鼠骨髓和脾脏中的 MDSC 数量明显高于正常小鼠，而脾脏中的 T 淋巴细胞数量明显减少。此外，BCC-Ex 明显促进了骨髓细胞或骨髓细胞衍生的巨噬细胞中 MDSCs 的分化，表现为 MDSCs 相关功能蛋白精氨酸酶-1（Arg-1）和诱导型一氧化氮合酶（iNOS）的表达增加。此外，BCC-Ex 显著下调了趋化因子受体 CXCR4 的表达，并显著上调了骨髓细胞和巨噬细胞中炎症细胞因子 IL-6 和 IL-10 的水平，显著抑制了 T 细胞的分裂和增殖。重要的是，CXCR4 激动剂 CXCL12 可逆转 BCC-Ex 的作用，表明 BCC-Ex 诱导的 MDSCs 可能依赖于 CXCR4 的下调。Western blot 显示，BCC-Ex 显著促进了骨髓细胞中 STAT3 的磷酸化，导致骨髓细胞增殖和凋亡受到抑制，骨髓细胞向 MDSCs 的分化加剧。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/56bca3cc98a7/JCMM-25-5497-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/d0649c036fcf/JCMM-25-5497-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/ccdaa15e7bbd/JCMM-25-5497-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/a97b7a837695/JCMM-25-5497-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/78cab8c779eb/JCMM-25-5497-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/05b85212954f/JCMM-25-5497-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/56bca3cc98a7/JCMM-25-5497-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/d0649c036fcf/JCMM-25-5497-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/e81a71518574/JCMM-25-5497-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/ccdaa15e7bbd/JCMM-25-5497-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/a97b7a837695/JCMM-25-5497-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/78cab8c779eb/JCMM-25-5497-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/05b85212954f/JCMM-25-5497-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/26ad/8184685/56bca3cc98a7/JCMM-25-5497-g002.jpg

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