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IL-21 介导的 NK 细胞耗竭逆转促进 MHC Ⅰ类缺陷肿瘤中的抗肿瘤免疫。

IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours.

机构信息

Laboratory of Immunology, Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea.

Laboratory of Immune Regulation, Research Institute of Pharmaceutical Science, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.

出版信息

Nat Commun. 2017 Jun 6;8:15776. doi: 10.1038/ncomms15776.

DOI:10.1038/ncomms15776
PMID:28585539
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5467212/
Abstract

During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours. During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients. Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy.

摘要

在癌症免疫编辑过程中，肿瘤中主要组织相容性复合体 I 类 (MHC-I) 的缺失导致肿瘤逃避宿主免疫系统的识别。最近的研究表明，在晚期癌症中发现的大多数自然杀伤 (NK) 细胞存在缺陷，使恶性 MHC-I 缺陷型肿瘤逃脱 NK 细胞依赖的免疫控制。在这里，我们展示了负载自然杀伤 T (NKT) 细胞配体的肿瘤抗原表达抗原呈递细胞 (APC) 疫苗可有效根除这些晚期肿瘤。在这个过程中，我们发现 Tim-3 和 PD-1 的共表达标志着晚期肿瘤中功能耗竭的 NK 细胞，并且肿瘤中 MHC-I 的下调与荷瘤小鼠和癌症患者中 NK 细胞耗竭的诱导密切相关。此外，IL-21 恢复 NK 细胞功能对于针对晚期肿瘤的疫苗的抗肿瘤作用至关重要。这些结果揭示了诱导晚期癌症中 NK 细胞功能障碍的过程，并为癌症免疫治疗策略的发展提供了指导。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/b87de15896b9/ncomms15776-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/1a6539e6026b/ncomms15776-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/f1c6d6028fe3/ncomms15776-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/e33b3cccd440/ncomms15776-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/ed1743c991c3/ncomms15776-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/32c237b4af12/ncomms15776-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/8c1c5b3125fa/ncomms15776-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/b87de15896b9/ncomms15776-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/1a6539e6026b/ncomms15776-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/f1c6d6028fe3/ncomms15776-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/e33b3cccd440/ncomms15776-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/ed1743c991c3/ncomms15776-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/32c237b4af12/ncomms15776-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/8c1c5b3125fa/ncomms15776-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e00/5467212/b87de15896b9/ncomms15776-f7.jpg

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[1]
IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours.

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[3]
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[4]
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[5]
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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

[1]
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Nat Med. 2016-12

[2]
PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma.

Oncotarget. 2016-11-8

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Nat Immunol. 2016-8-19

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J Allergy Clin Immunol. 2016-5-27

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Nature. 2016-6-1

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Sci Transl Med. 2016-3-2

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Cancer Cell. 2015-4-13

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Science. 2015-5-15

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