Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer

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Abstract

GARP (glycoprotein-A repetitions predominant) is a type I transmembrane cell surface docking receptor for latent transforming growth factor-β (TGF-β) that is abundantly expressed on regulatory T lymphocytes and platelets. GARP regulates the availability of membrane-bound latent TGF-β and modulates its activation. For this reason, GARP expression on immune and non-immune cells is involved in maintaining peripheral tolerance. It plays an important role in preventing inflammatory diseases such as allergy and graft versus host disease (GvHD). GARP is also frequently hijacked by cancer cells to promote oncogenesis. This review summarizes the most important features of GARP biology described to date including gene regulation, protein expression and mechanism in activating latent TGF-β, and the function of GARP in regulatory T cell biology and peripheral tolerance, as well as GARP’s increasingly recognized roles in platelet-mediated cancer immune evasion. The promise for GARP-targeted strategy as a novel immunotherapy of cancer is also highlighted.

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Transforming growth factor-beta regulation of immune responses.

Ming O Li, Yisong Y Wan, Shomyseh Sanjabi … (2006)

Transforming growth factor-beta (TGF-beta) is a potent regulatory cytokine with diverse effects on hemopoietic cells. The pivotal function of TGF-beta in the immune system is to maintain tolerance via the regulation of lymphocyte proliferation, differentiation, and survival. In addition, TGF-beta controls the initiation and resolution of inflammatory responses through the regulation of chemotaxis, activation, and survival of lymphocytes, natural killer cells, dendritic cells, macrophages, mast cells, and granulocytes. The regulatory activity of TGF-beta is modulated by the cell differentiation state and by the presence of inflammatory cytokines and costimulatory molecules. Collectively, TGF-beta inhibits the development of immunopathology to self or nonharmful antigens without compromising immune responses to pathogens. This review highlights the findings that have advanced our understanding of TGF-beta in the immune system and in disease.

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Tumor-associated macrophages: from basic research to clinical application

Li-Li Yang, Yi Zhang (2017)

The fact that various immune cells, including macrophages, can be found in tumor tissues has long been known. With the introduction of concept that macrophages differentiate into a classically or alternatively activated phenotype, the role of tumor-associated macrophages (TAMs) is now beginning to be elucidated. TAMs act as “protumoral macrophages,” contributing to disease progression. TAMs can promote initiation and metastasis of tumor cells, inhibit antitumor immune responses mediated by T cells, and stimulate tumor angiogenesis and subsequently tumor progression. As the relationship between TAMs and malignant tumors becomes clearer, TAMs are beginning to be seen as potential biomarkers for diagnosis and prognosis of cancers, as well as therapeutic targets in these cases. In this review, we will discuss the origin, polarization, and role of TAMs in human malignant tumors, as well as how TAMs can be used as diagnostic and prognostic biomarkers and therapeutic targets of cancer in clinics.

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Latent TGF-β structure and activation.

Minlong Shi, Jianghai Zhu, Rui Wang … (2011)

Transforming growth factor (TGF)-β is stored in the extracellular matrix as a latent complex with its prodomain. Activation of TGF-β1 requires the binding of α(v) integrin to an RGD sequence in the prodomain and exertion of force on this domain, which is held in the extracellular matrix by latent TGF-β binding proteins. Crystals of dimeric porcine proTGF-β1 reveal a ring-shaped complex, a novel fold for the prodomain, and show how the prodomain shields the growth factor from recognition by receptors and alters its conformation. Complex formation between α(v)β(6) integrin and the prodomain is insufficient for TGF-β1 release. Force-dependent activation requires unfastening of a 'straitjacket' that encircles each growth-factor monomer at a position that can be locked by a disulphide bond. Sequences of all 33 TGF-β family members indicate a similar prodomain fold. The structure provides insights into the regulation of a family of growth and differentiation factors of fundamental importance in morphogenesis and homeostasis.

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Author and article information

Contributors

Alessandra Metelli: metellia@musc.edu

Mohammad Salem: salemmo@musc.edu

Caroline H. Wallace: wallacc@musc.edu

Bill X. Wu: wub@musc.edu

Anqi Li: lian@musc.edu

Xue Li: sean.li@childrens.harvard.edu

Zihai Li: zihai@musc.edu

Journal

Journal ID (nlm-ta): J Hematol Oncol

Journal ID (iso-abbrev): J Hematol Oncol

Title: Journal of Hematology & Oncology

Publisher: BioMed Central (London )

ISSN (Electronic): 1756-8722

Publication date (Electronic): 20 February 2018

Publication date PMC-release: 20 February 2018

Publication date Collection: 2018

Volume: 11

Electronic Location Identifier: 24

Affiliations

[1 ]ISNI 0000 0001 2189 3475, GRID grid.259828.c, Department of Microbiology and Immunology, Hollings Cancer Center, , Medical University of South Carolina, ; Charleston, SC 29425 USA

[2 ]Children’s Hospital Boston, Harvard Medical School, Boston, MA 02115 USA

[3 ]ISNI 0000 0001 2189 3846, GRID grid.207374.5, The First Affiliated Hospital, Zhengzhou University School of Medicine, ; Zhengzhou, 450052 China

Article

Publisher ID: 570

DOI: 10.1186/s13045-018-0570-z

PMC ID: 5819195

PubMed ID: 29458436

SO-VID: afbf2c1c-3b5d-44df-bc6f-ff730120f5e0

License:

Open Access This 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 : 3 January 2018

Date accepted : 6 February 2018

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: CA186866

Award ID: CA213290

Award ID: CA188419

Award ID: AI077283

Award Recipient : Zihai Li

Funded by: FundRef http://dx.doi.org/10.13039/100006806, Hollings Cancer Center, Medical University of South Carolina;

Award ID: P30CA138313

Award Recipient : Zihai Li

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tgf-β,garp,treg,immune tolerance,cancer,platelets

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: tgf-β, garp, treg, immune tolerance, cancer, platelets

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Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer

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Karger: Oncology

Most cited references 81

Transforming growth factor-beta regulation of immune responses.

Tumor-associated macrophages: from basic research to clinical application

Latent TGF-β structure and activation.

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Cited by 45

Most referenced authors 2,704