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CD47阻断引发T细胞介导的免疫原性肿瘤破坏。

CD47 blockade triggers T cell-mediated destruction of immunogenic tumors.

作者信息

Liu Xiaojuan, Pu Yang, Cron Kyle, Deng Liufu, Kline Justin, Frazier William A, Xu Hairong, Peng Hua, Fu Yang-Xin, Xu Meng Michelle

机构信息

Institute of Biophysics and the University of Chicago Joint Group for Immunotherapy, Chinese Academy of Science Key Laboratory for Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.

University of Chinese Academy of Sciences, Beijing, China.

出版信息

Nat Med. 2015 Oct;21(10):1209-15. doi: 10.1038/nm.3931. Epub 2015 Aug 31.


DOI:10.1038/nm.3931
PMID:26322579
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4598283/
Abstract

Macrophage phagocytosis of tumor cells mediated by CD47-specific blocking antibodies has been proposed to be the major effector mechanism in xenograft models. Here, using syngeneic immunocompetent mouse tumor models, we reveal that the therapeutic effects of CD47 blockade depend on dendritic cell but not macrophage cross-priming of T cell responses. The therapeutic effects of anti-CD47 antibody therapy were abrogated in T cell-deficient mice. In addition, the antitumor effects of CD47 blockade required expression of the cytosolic DNA sensor STING, but neither MyD88 nor TRIF, in CD11c+ cells, suggesting that cytosolic sensing of DNA from tumor cells is enhanced by anti-CD47 treatment, further bridging the innate and adaptive responses. Notably, the timing of administration of standard chemotherapy markedly impacted the induction of antitumor T cell responses by CD47 blockade. Together, our findings indicate that CD47 blockade drives T cell-mediated elimination of immunogenic tumors.

摘要

CD47特异性阻断抗体介导的巨噬细胞对肿瘤细胞的吞噬作用被认为是异种移植模型中的主要效应机制。在此,我们使用同基因免疫活性小鼠肿瘤模型,揭示了CD47阻断的治疗效果取决于树突状细胞而非巨噬细胞对T细胞反应的交叉启动。抗CD47抗体疗法的治疗效果在T细胞缺陷小鼠中被消除。此外,CD47阻断的抗肿瘤作用需要CD11c⁺细胞中胞质DNA传感器STING的表达,但不需要MyD88或TRIF,这表明抗CD47治疗增强了对肿瘤细胞DNA的胞质感知,进一步连接了先天免疫和适应性免疫反应。值得注意的是,标准化疗的给药时间显著影响了CD47阻断诱导的抗肿瘤T细胞反应。总之,我们的研究结果表明,CD47阻断可驱动T细胞介导的免疫原性肿瘤清除。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/44f75f0d942c/nihms710815f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/4ca8303a5ddf/nihms710815f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/d6b01d2c0002/nihms710815f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/e04a0aae45c8/nihms710815f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/197907fb74ae/nihms710815f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/700c5805e975/nihms710815f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/44f75f0d942c/nihms710815f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/4ca8303a5ddf/nihms710815f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/d6b01d2c0002/nihms710815f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/e04a0aae45c8/nihms710815f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/197907fb74ae/nihms710815f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/700c5805e975/nihms710815f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9729/4598283/44f75f0d942c/nihms710815f6.jpg

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本文引用的文献

[1]
STING-Dependent Cytosolic DNA Sensing Promotes Radiation-Induced Type I Interferon-Dependent Antitumor Immunity in Immunogenic Tumors.

Immunity. 2014-11-20

[2]
STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors.

Immunity. 2014-11-20

[3]
Genetic basis for clinical response to CTLA-4 blockade in melanoma.

N Engl J Med. 2014-12-4

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CD47 in the tumor microenvironment limits cooperation between antitumor T-cell immunity and radiotherapy.

Cancer Res. 2014-10-8

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Targeting the tumor microenvironment with interferon-β bridges innate and adaptive immune responses.

Cancer Cell. 2014-1-13

[6]
CCL2/CCR2-dependent recruitment of functional antigen-presenting cells into tumors upon chemotherapy.

Cancer Res. 2013-12-3

[7]
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Annu Rev Immunol. 2013-11-6

[8]
Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects.

Science. 2013-8-29

[9]
Engineered SIRPα variants as immunotherapeutic adjuvants to anticancer antibodies.

Science. 2013-5-30

[10]
Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response.

Proc Natl Acad Sci U S A. 2013-5-20

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