Mini-Review: GARP, a Putative Potential Molecule in Tumor Immunosuppressive Environment

Guo M, Wu W, Liu W, Ren F. Mini-Review: GARP, a Putative Potential Molecule in Tumor Immunosuppressive Environment. J Cancer Treat & Diagnosis. (2019);3(1):14-18 Journal of Cancer Treatment and Diagnosis Mini Review Open Access Mini-Review: GARP, a Putative Potential Molecule in Tumor Immunosuppressive Environment Miao Guo1, Wei Wu5, Wei Liu2, 3*, Fu Ren2, 3, 4# 1Department of Clinical Laboratory, the First Affiliated Hospital of Jinzhou Medical University, Jinzhou 121001, Liaoning, China 2Biological Anthropology Institute, Jinzhou Medical University, No.40, Section 3, Songpo Road, Linghe District, Jinzhou 121001, Liaoning, China 3Liaoning Province Key Laboratory of Chinese Physical Characteristics Research (LPKL-CPCR), Jinzhou 121001, Liaoning, China 4Department of Anatomy, College of Basic Medical Sciences of Jinzhou Medical University, Jinzhou 121001, Liaoning, China 5School of Humanities and Management, Jinzhou Medical University, Jinzhou, Liaoning, China 121001 Article Info ABSTRACT Article Notes Glycoprotein A Repetitions Predominant (GARP), also known as Received: December 20, 2018 leucine-rich repeats containing 32 (LRRC32), is a transmembrane protein Accepted: January 30, 2019 that presents latent TGF-β1 on the surface of regulatory T cells (Tregs) and *Correspondence: modulates its activation in tumor immunosuppressive environment. Tregs Dr. Wei Liu, Biological Anthropology Institute, Jinzhou are immunosuppressive immune cells that play an important role in tumor Medical University, No.40, Section 3, Songpo Road, Linghe development and progression. Inhibition of Treg function is considered to be District, Jinzhou, Liaoning, P. R. 121001, China; E-mail: an effective strategy for antitumor therapy. In addition to its expression in [email protected]. Tregs, GARP has been recently found to be highly expressed in a few types of # Correspondence: human solid tumor tissues, yet the role of its expression in tumor tissues or Dr. Fu Ren, Biological Anthropology Institute, Jinzhou cells remains unknown. Most previous studies on GARP have focused on GARP Medical University, No.40, Section 3, Songpo Road, Linghe function in Tregs and the role of GARP in latent TGF-β1 activation. The present District, Jinzhou, Liaoning, P. R. 121001, China; E-mail: review provides an up to date overview of GARP expression and its potential [email protected]. role in tumor cells and tissues. ©2019 Liu W*, Ren F#. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License Introduction . Regulatory T cells (Tregs) are a small population of CD4+ T Key words: lymphocytes and play an important role in tumor development and GARP progression1. Activation or enhancement of Treg function is one of the Foxp3 main mechanisms by which cancer evades antitumor immune attacks Tregs Tumor through a variety of different pathways. Inhibition of Treg function Cancer is also considered to be an effective antitumor treatment strategy. andPrevious poor studiesprognosis have2-4. shownHowever a significant further studies association of Tregs of isexpression limited by of a Treg specific markers (Foxp3, and CD39) with lymph node metastasis important in the development and function of Tregs5 intracellularlyof lack of available in both markers Tregs for andactivated conventional Tregs. Although T cells 6-8Foxp3 is very , it is expressed , making it mechanismschallenging to ofisolate Tregs. and Glycoproteinfurther characterize A Repetitions Tregs. Specific Predominant markers for activated Tregs are therefore necessary for research in the specific contribute(GARP), also to knownan immunosuppressive as leucine-rich repeats tumor containing microenvironment 32 (LRRC32),. It has beenbeen demonstratedwidely accepted that to GARP be a ismarker the cell of surface activated docking Tregs, receptor which9,10 11. for latent TGF-β and exerts its antitumor function, at least in part, by activatingTGF-β and TGF-β GARP in tumor microenvironment Transforming growth factor-β family members (TGF-β1, TGF-β2 Page 14 of 18 Guo M, Wu W, Liu W, Ren F. Mini-Review: GARP, a Putative Potential Molecule in Tumor Immunosuppressive Environment. J Cancer Treat & Diagnosis. (2019);3(1):14-18 Journal of Cancer Treatment and Diagnosis cells and are found in all tissues. They play a key role in . and TGF-β3) are pleiotropic cytokines expressed by most 3p, miR-181a, miR-185, miR-24, and miR-335 are thought35,36 12 to bind to the 3’ UTR of GARP to repress its expression arecell associatedproliferation, with differentiation, a variety of migration,pathological invasion conditions and degradationThereafter, ofmiR-142-3p GARP mRNA. represses The Argonaute posttranscriptional protein family immune function, etc . Dysregulations in TGF-β function regulation of GARP expression by Argonaute 2-associated including cancer. TGF-β2 and TGF-β3 are mainly involved plays a central role in RNA silencing processes, as essential in embryonic development. TGF-β1 has been extensively components of the RNA-induced silencing complex (RISC). studied in regulating the immune response. Biochemically, Argonaute 2 binds miR-142-3p, which guides Argonaute TGF-β exists in at least four different forms: (1) freely 2 to the 3’ untranslated region of GARP through sequence soluble TGF-β; (2) soluble TGF-β associated with latency- complementarity, which then leads to GARP mRNA cleavage associated peptide (LAP), known as latent TGF-β (LTGF-β); or translation inhibition. Downregulation of miRNA, in (3) TGF-β-LAP-LTBP, latent TGF-β associated with latent turn,GARP may Protein be one and way Expressionto induce GARP expression in Tregs. TGF-β-binding protein (LTBP);13,14 and (4) membrane- associated latent form of TGF-β . Only TGF-β without LAP of 662 amino acids. Its structure can be divided into three ofis knownGARP toincreases be biologically the inhibitory active. GARP function is highly of expressed Tregs15. GARP is an 80kD transmembrane protein consisting on the surface of activated Tregs and the overexpression regions: the extracellular domain with leucine-rich repeats, GARP can bind to latent16,17 TGF-β and promote secretion and acidaccounting residues for about. Tregs 70% frequently of the protein; accumulate the hydrophobicin the tumor mediatesactivation theof TGF-β1 accumulation. Additionally, and subsequent GARP protein activation is also of tissuestransmembrane and peripheral10,25 domain; blood and of cytoplasmic patients with tail cancer. of 15 amino Their found to be expressed11. By regulating on human innate tumor and cells adaptive where immune it likely increased frequency has generally been considered to be latent TGF-β to the Treg-mediated antitumour immunosuppression1. components and facilitating tumor immune evasion, GARP the marker of poor cancer prognosis, presumably due growthprovides and an progressionexcellent TGF-β of cancer reservoir cells. that In terms plays ofa roleinnate in the tumor microenvironment, thereby supporting the GARP is co-expressed with latent TGF-β on the surface of. (NK) cells and dendritic (DC) cells activated Tregs, but not on other types of T cells and16,37,38 is impairsimmunity, the TGF-β adaptive inhibits antitumor the maturation18,19 immunity of natural by directly killer thus regarded as a specific marker of activated Tregs . Furthermore, TGF-β inIn patientsone study, with as aadvanced TGF-β docking hepatocellular receptor, carcinoma the number than of GARP+Foxp3+ Tregs was found to be significantly higher inhibiting the clonal expansion20,21 and cytotoxicity of the . confersCD8+ cytotoxic a regulatory T cells(CTLs) and immune. Finally, suppressive TGF-β phenotype indirectly in the control group. Furthermore, the GARP expression39 toattenuates CD4+ T cells CTLs22 by. inducing the expression of Foxp3, which GARPlevels ofin Foxp3+Tregs was Tregs increased were elevated in tumor in thesetissues patients of lung cancerCompared patients with andthe wascontrol associated group, thewith expression lymph node of GARP Gene and Expression . These 40 GARPmetastasis, promotes distant cancer metastasis progression and clinicalthrough stage activation of The GARP-encoding gene LRRC32 was firstly identified study findings indicate that increased expression of as DI1S863E in the human 11q13.5-q14 chromosomal breastregion cancerand 23,24defined on chromosome 7 in the region 7E- immunosuppressive functions of Tregs. More interestingly, 7F in mice 9,10. LRRC32 gene is frequently amplified in in a clinical study of advanced gastric cancer, the tumor . It consists of two encoding exons and is thantissue that infiltration of the control of Foxp3+ group 41and GARP+Tregs in the expressed at two major transcripts of 4.4 and 2.8 kb. The25. neoadjuvant chemotherapy group was significantly lower first exon encodes the signal peptide and nine amino acids, . Monoclonal antibodies and the second exon encodes most of the coding region alsoagainst inhibited GARP in the GARP/TGF-β1complexes immunosuppressive activity not only of blockedhuman andGARP lymphoid gene is tissuesexpressed in a variety of tissues including Tregsthe production in a mouse of model active of TGF-β1 Xenogeneic by humangraft -versus-host Tregs but placenta, lung, kidney,10 heart, liver, skeletal muscle, pancreas disease42. One study however reported that only deletion Tregs . In addition, and hepaticGARP gene stellate is detected cells26,27 in multiple15,28 cell types such as29,30 megakaryocytes, platelets. Single31, immunosuppressive function in vivo . nucleotide, endothelial polymorphisms cells

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