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宿主 STING 依赖性髓系来源抑制细胞动员导致外辐射抵抗。

Host STING-dependent MDSC mobilization drives extrinsic radiation resistance.

机构信息

Ludwig Center for Metastasis Research, Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, 60637, USA.

Shanghai Institute of Immunology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, 280 South, Chongqing Road, Shanghai, 200025, China.

出版信息

Nat Commun. 2017 Nov 23;8(1):1736. doi: 10.1038/s41467-017-01566-5.

DOI:10.1038/s41467-017-01566-5
PMID:29170400
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5701019/
Abstract

Radiotherapy induces and promotes innate and adaptive immunity in which host STING plays an important role. However, radioresistance in irradiated tumors can also develop, resulting in relapse. Here we report a mechanism by which extrinsic resistance develops after local ablative radiation that relies on the immunosuppressive action of STING. The STING/type I interferon pathway enhances suppressive inflammation in tumors by recruiting myeloid cells in part via the CCR2 pathway. Germ-line knockouts of CCR2 or treatment with an anti-CCR2 antibody results in blockade of radiation-induced MDSC infiltration. Treatment with anti-CCR2 antibody alleviates immunosuppression following activation of the STING pathway, enhancing the anti-tumor effects of STING agonists and radiotherapy. We propose that radiation-induced STING activation is immunosuppressive due to (monocytic) M-MDSC infiltration, which results in tumor radioresistance. Furthermore, the immunosuppressive effects of radiotherapy and STING agonists can be abrogated in humans by a translational strategy involving anti-CCR2 antibody treatment to improve radiotherapy.

摘要

放射治疗可诱导和促进先天免疫和适应性免疫，其中宿主 STING 发挥着重要作用。然而，放射治疗后的肿瘤也可能产生放射抵抗，导致复发。在这里，我们报告了一种在局部消融放射后产生外在抵抗的机制，该机制依赖于 STING 的免疫抑制作用。STING/Ⅰ型干扰素途径通过 CCR2 途径部分地通过募集髓样细胞来增强肿瘤中的抑制性炎症。CCR2 的种系敲除或用抗 CCR2 抗体治疗可导致放射诱导的 MDSC 浸润受阻。激活 STING 途径后，用抗 CCR2 抗体治疗可减轻免疫抑制，增强 STING 激动剂和放射治疗的抗肿瘤作用。我们提出，放射诱导的 STING 激活是由于（单核细胞）M-MDSC 浸润而具有免疫抑制性，这导致了肿瘤的放射抵抗。此外，通过涉及抗 CCR2 抗体治疗的转化策略，可以消除放射治疗和 STING 激动剂的免疫抑制作用，从而改善放射治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/e459e5a76bab/41467_2017_1566_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/19bfaeea83e7/41467_2017_1566_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/33dfaf9c0121/41467_2017_1566_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/2b016d28df4c/41467_2017_1566_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/ae70a3f733c6/41467_2017_1566_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/0b88bd52f8c7/41467_2017_1566_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/e459e5a76bab/41467_2017_1566_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/19bfaeea83e7/41467_2017_1566_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/33dfaf9c0121/41467_2017_1566_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/2b016d28df4c/41467_2017_1566_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/ae70a3f733c6/41467_2017_1566_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/0b88bd52f8c7/41467_2017_1566_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8c12/5701019/e459e5a76bab/41467_2017_1566_Fig6_HTML.jpg

相似文献

[1]
Host STING-dependent MDSC mobilization drives extrinsic radiation resistance.

Nat Commun. 2017-11-23

[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[2]
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[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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本文引用的文献

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Radiotherapy and immunotherapy: a beneficial liaison?

Nat Rev Clin Oncol. 2017-1-17

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STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors.

Immunity. 2014-11-20

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STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors.

Immunity. 2014-11-20

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