Natural killer group 2D receptor and its ligands in cancer immune escape

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Abstract

The immune system plays important roles in tumor development. According to the immune-editing theory, immune escape is the key to tumor survival, and exploring the mechanisms of tumor immune escape can provide a new basis for the treatment of tumors. In this review, we describe the mechanisms of natural killer group 2D (NKG2D) receptor and NKG2D ligand (NKG2DL) in tumor immune responses.

Natural killer (NK) cells are important cytotoxic cells in the immune system, and the activated NKG2D receptor on the NK cell surface can bind to NKG2DL expressed in tumor cells, enabling NK cells to activate and kill tumor cells. However, tumors can escape the immune clearance mediated by NKG2D receptor/NKG2DL through various mechanisms. The expression of NKG2D receptor on NK cells can be regulated by cells, molecules, and hypoxia in the tumor microenvironment. Tumor cells regulate the expression of NKG2DL at the level of transcription, translation, and post-translation and thereby escape recognition by NK cells. In particular, viruses and hormones have special mechanisms to affect the expression of NKG2D receptor and NKG2DL. Therefore , NKG2D\NKG2DL may have applications as targets for more effective antitumor therapy.

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Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells.

Andrea Facciabene, Xiaohui Peng, Ian S Hagemann … (2011)

Although immune mechanisms can suppress tumour growth, tumours establish potent, overlapping mechanisms that mediate immune evasion. Emerging evidence suggests a link between angiogenesis and the tolerance of tumours to immune mechanisms. Hypoxia, a condition that is known to drive angiogenesis in tumours, results in the release of damage-associated pattern molecules, which can trigger the rejection of tumours by the immune system. Thus, the counter-activation of tolerance mechanisms at the site of tumour hypoxia would be a crucial condition for maintaining the immunological escape of tumours. However, a direct link between tumour hypoxia and tolerance through the recruitment of regulatory cells has not been established. We proposed that tumour hypoxia induces the expression of chemotactic factors that promote tolerance. Here we show that tumour hypoxia promotes the recruitment of regulatory T (T(reg)) cells through induction of expression of the chemokine CC-chemokine ligand 28 (CCL28), which, in turn, promotes tumour tolerance and angiogenesis. Thus, peripheral immune tolerance and angiogenesis programs are closely connected and cooperate to sustain tumour growth. ©2011 Macmillan Publishers Limited. All rights reserved

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The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy

Sourav Paul, Girdhari Lal (2017)

Natural killer (NK) cells are innate immune cells that show strong cytolytic function against physiologically stressed cells such as tumor cells and virus-infected cells. NK cells show a broad array of tissue distribution and phenotypic variability. NK cells express several activating and inhibitory receptors that recognize the altered expression of proteins on target cells and control the cytolytic function. NK cells have been used in several clinical trials to control tumor growth. However, the results are encouraging only in hematological malignancies but not very promising in solid tumors. Increasing evidence suggests that tumor microenvironment regulate the phenotype and function of NK cells. In this review, we discussed the NK cell phenotypes and its effector function and impact of the tumor microenvironment on effector and cytolytic function of NK cells. We also summarized various NK cell-based immunotherapeutic strategies used in the past and the possibilities to improve the function of NK cell for the better clinical outcome.

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Natural killer cell cytotoxicity is suppressed by exposure to the human NKG2D ligand MICA*008 that is shed by tumor cells in exosomes.

Omodele Ashiru, Philippe Boutet, Lola Fernández-Messina … (2010)

The MHC class I-related chain (MIC) A and MICB ligands for the activating receptor NKG2D can be shed from tumor cells, and the presence of these soluble molecules in sera is related with compromised immune response and progression of disease. Recently, thiol disulphide isomerases and members of the ADAM (a disintegrin and metalloproteinase) gene family were identified as key enzymes in mediating MICA/B shedding from cells. Here, we report shedding of the most frequently expressed MICA allele in human populations (MICA*008) into exosomes, small membrane vesicles that are secreted upon fusion with the plasma membrane. Although similar to other MICA/B molecules in the extracellular domain, the predicted transmembrane and cytoplasmic domains of MICA*008 are quite different, and this difference seemed to be critical for the mode of release from tumor cells. Treatment of natural killer (NK) cells with exosomes containing MICA*008 molecules not only triggered downregulation of NKG2D from the cell surface but also provoked a marked reduction in NK cytotoxicity that is independent of NKG2D ligand expression by the target cell. Our findings reveal a mechanism of NK suppression in cancer that may facilitate immune escape and progression.

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Author and article information

Contributors

Wei Xiong: 86-731-8480-5446 , xiongwei@csu.edu.cn

Fuyan Wang: 86-731-8480-5446 , wfy4010@163.com

Journal

Journal ID (nlm-ta): Mol Cancer

Journal ID (iso-abbrev): Mol. Cancer

Title: Molecular Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1476-4598

Publication date (Electronic): 27 February 2019

Publication date PMC-release: 27 February 2019

Publication date Collection: 2019

Volume: 18

Electronic Location Identifier: 29

Affiliations

[1 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, NHC Key Laboratory of Carcinogenesis (Central South University) and Hunan Key Laboratory of Translational Radiation Oncology, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, , Central South University, ; Changsha, Hunan China

[2 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, The Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, , Central South University, ; Changsha, Hunan China

[3 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Disease Genome Research Center, the Third Xiangya Hospital, , Central South University, ; Changsha, Hunan China

[4 ]ISNI 0000 0001 0675 4725, GRID grid.239578.2, Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, ; Cleveland, OH USA

[5 ]ISNI 0000 0001 0379 7164, GRID grid.216417.7, Department of Immunology, School of Basic Medical Science, , Central South University, ; Changsha, Hunan China

Article

Publisher ID: 956

DOI: 10.1186/s12943-019-0956-8

PMC ID: 6391774

PubMed ID: 30813924

SO-VID: c158be57-3a37-430b-8fd2-40732ced7295

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 21 November 2018

Date accepted : 11 February 2019

Funding

Funded by: The National Natural Science Foundation of China

Award ID: 81572787, 81672683, 81672993, 81672688, 81702907, 81772901, 81772928 81803025, and 81872278

Award Recipient : Wei Xiong

Funded by: the Overseas Expertise Introduction Project for Discipline Innovation

Award ID: 111 Project, No. 111–2-12

Award Recipient : Wei Xiong

Funded by: the Natural Science Foundation of Hunan Province

Award ID: 2016JC2035, 2017SK2105, 2018JJ3704, 2018JJ3815, 2018SK21210 and 2018SK21211

Award Recipient : Wei Xiong

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tumor,tumor escape,tumor microenvironment,natural killer cell,natural killer group 2d ligand,natural killer group 2d receptor

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tumor, tumor escape, tumor microenvironment, natural killer cell, natural killer group 2d ligand, natural killer group 2d receptor

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