GARP: A Key Target to Evaluate Tumor Immunosuppressive Microenvironment

Alexanne Bouchard ¹, Bertrand Collin ¹, Carmen Garrido ¹, Pierre-Simon Bellaye ¹, Evelyne Kohli ²

Affiliations

¹ Centre George-François Leclerc, Service de Médecine Nucléaire, Plateforme d'Imagerie et de Radiothérapie Précliniques, 1 rue du Professeur Marion, 21079 Dijon, France.
² UMR INSERM/uB/AGROSUP 1231, Labex LipSTIC, Faculty of Health Sciences, Université de Bourgogne Franche-Comté, 21079 Dijon, France.

PMID: 34571713
75 References
2 citations

Abstract

Glycoprotein-A repetitions predominant (GARP) is the docking receptor for latent transforming growth factor (LTGF-β) and promotes its activation. In cancer, increased GARP expression has been found in many types of cancer. GARP is expressed by regulatory T cells and platelets in the tumor microenvironment (TME) and can be also expressed by tumor cells themselves. Thus, GARP can be widely present in tumors in which it plays a major role in the production of active TGF-β, contributing to immune evasion and cancer progression via the GARP-TGF-β pathway. The objective of this review is to highlight GARP expression and function in cancer and to evaluate the potential of membrane GARP as a predictive and therapeutic follow-up biomarker that could be assessed, in real time, by molecular imaging. Moreover, as GARP can be secreted, a focus will also be made on soluble GARP as a circulating biomarker.

Keywords: GARP; TGF-β; biomarker; cancer; immunosuppression.

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References
The GARP gene encodes a new member of the family of leucine-rich repeat-containing proteins. V Ollendorff, T Noguchi, O deLapeyriere, D Birnbaum. Cell Growth Differ, 1994 Feb 01; 5(2). PMID: 8180135
Immunoregulatory functions and the therapeutic implications of GARP-TGF-β in inflammation and cancer. Alessandra Metelli, Mohammad Salem, +4 authors, Zihai Li. less J Hematol Oncol, 2018 Feb 21; 11(1). PMID: 29458436 Free PMC article. Review.
Soluble GARP has potent antiinflammatory and immunomodulatory impact on human CD4⁺ T cells. Susanne A Hahn, Heiko F Stahl, +4 authors, Helmut Jonuleit. less Blood, 2013 Jul 03; 122(7). PMID: 23818544
Thrombin contributes to cancer immune evasion via proteolysis of platelet-bound GARP to activate LTGF-β. Alessandra Metelli, Bill X Wu, +15 authors, Zihai Li. less Sci Transl Med, 2020 Jan 10; 12(525). PMID: 31915300 Free PMC article.
TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Sanjeev Mariathasan, Shannon J Turley, +39 authors, Thomas Powles. less Nature, 2018 Feb 15; 554(7693). PMID: 29443960 Free PMC article. Highly Cited.
CD83 expression in CD4+ T cells modulates inflammation and autoimmunity. Simone Reinwald, Carsten Wiethe, +6 authors, Wiebke Hansen. less J Immunol, 2008 Apr 22; 180(9). PMID: 18424708
Array-comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas. Chung-Ji Liu, Shu-Chun Lin, +2 authors, Yann-Jang Chen, Kuo-Ming Chang, Kuo-Wei Chang. less Mol Carcinog, 2006 May 06; 45(10). PMID: 16676365
Increased Expression of GARP in Papillary Thyroid Carcinoma. Xiaoxu Zhang, Miao Guo, +4 authors, Fu Ren. less Endocr Pathol, 2018 Nov 18; 30(1). PMID: 30443770
Targeting TGF-β Signaling for Therapeutic Gain. Rosemary J Akhurst. Cold Spring Harb Perspect Biol, 2017 Mar 02; 9(10). PMID: 28246179 Free PMC article. Highly Cited. Review.
DNA amplification at 11q13.5-q14 in human breast cancer. P Szepetowski, V Ollendorff, +4 authors, P Gaudray. less Oncogene, 1992 Dec 01; 7(12). PMID: 1461654
Quantitative proteome analysis of human plasma following in vivo lipopolysaccharide administration using 16O/18O labeling and the accurate mass and time tag approach. Wei-Jun Qian, Matthew E Monroe, +15 authors, Inflammation and the Host Response to Injury Large Scale Collaborative Research Program. less Mol Cell Proteomics, 2005 Mar 09; 4(5). PMID: 15753121 Free PMC article.
Structure and developmental expression of mouse Garp, a gene encoding a new leucine-rich repeat-containing protein. R Roubin, S Pizette, +3 authors, V Ollendorff, J Planche, D Birnbaum, O Delapeyriere. less Int J Dev Biol, 1996 Jun 01; 40(3). PMID: 8840187
Platelet-derived transforming growth factor-beta down-regulates NKG2D thereby inhibiting natural killer cell antitumor reactivity. Hans-Georg Kopp, Theresa Placke, Helmut Rainer Salih. Cancer Res, 2009 Sep 10; 69(19). PMID: 19738039 Highly Cited.
Expression of GARP Is Increased in Tumor-Infiltrating Regulatory T Cells and Is Correlated to Clinicopathology of Lung Cancer Patients. Hao Jin, Liping Sun, +2 authors, Lu Tang, Wenwen Yu, Hui Li. less Front Immunol, 2017 Mar 07; 8. PMID: 28261204 Free PMC article.
Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin αVβ8. Julie Stockis, Stéphanie Liénart, +5 authors, Sophie Lucas. less Proc Natl Acad Sci U S A, 2017 Nov 08; 114(47). PMID: 29109269 Free PMC article.
Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Suresh Kalathil, Amit A Lugade, +2 authors, Austin Miller, Renuka Iyer, Yasmin Thanavala. less Cancer Res, 2013 Feb 21; 73(8). PMID: 23423978 Free PMC article. Highly Cited.
Contribution of platelets to tumour metastasis. Laurie J Gay, Brunhilde Felding-Habermann. Nat Rev Cancer, 2011 Jan 25; 11(2). PMID: 21258396 Free PMC article. Highly Cited. Review.
GARP regulates the bioavailability and activation of TGFβ. Rui Wang, Jianghai Zhu, +3 authors, Xianchi Dong, Minlong Shi, Chafen Lu, Timothy A Springer. less Mol Biol Cell, 2012 Jan 27; 23(6). PMID: 22278742 Free PMC article.
Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer. Grégoire de Streel, Charlotte Bertrand, +17 authors, Sophie Lucas. less Nat Commun, 2020 Sep 13; 11(1). PMID: 32917858 Free PMC article.
Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer. Qianghua Hu, Takeshi Hisamatsu, +8 authors, Vahid Afshar-Kharghan. less Clin Cancer Res, 2017 Jun 15; 23(18). PMID: 28611202 Free PMC article.
Noninvasive Imaging of CD206-Positive M2 Macrophages as an Early Biomarker for Post-Chemotherapy Tumor Relapse and Lymph Node Metastasis. Chenran Zhang, Xinhe Yu, +8 authors, Zhaofei Liu. less Theranostics, 2017 Nov 22; 7(17). PMID: 29158825 Free PMC article.
The HSP GRP94 interacts with macrophage intracellular complement C3 and impacts M2 profile during ER stress. Killian Chaumonnot, Sophie Masson, +6 authors, Evelyne Kohli. less Cell Death Dis, 2021 Jan 24; 12(1). PMID: 33483465 Free PMC article.
Constitutive production and thrombin-induced release of vascular endothelial growth factor by human megakaryocytes and platelets. R Möhle, D Green, +2 authors, M A Moore, R L Nachman, S Rafii. less Proc Natl Acad Sci U S A, 1997 Jan 21; 94(2). PMID: 9012841 Free PMC article. Highly Cited.
Comparative gene expression profiling of in vitro differentiated megakaryocytes and erythroblasts identifies novel activatory and inhibitory platelet membrane proteins. Iain C Macaulay, Marloes R Tijssen, +10 authors, Willem H Ouwehand. less Blood, 2006 Dec 29; 109(8). PMID: 17192395 Free PMC article.
Mechanistic basis and clinical relevance of the role of transforming growth factor-β in cancer. Run-Long Lin, Lu-Jun Zhao. Cancer Biol Med, 2016 Jan 19; 12(4). PMID: 26779375 Free PMC article. Review.
Specificity, versatility, and control of TGF-β family signaling. Rik Derynck, Erine H Budi. Sci Signal, 2019 Feb 28; 12(570). PMID: 30808818 Free PMC article. Highly Cited. Review.
Platelets: physiology and biochemistry. Kerstin Jurk, Beate E Kehrel. Semin Thromb Hemost, 2005 Sep 09; 31(4). PMID: 16149014 Review.
Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Ye Zheng, Steven Josefowicz, +3 authors, Alexander Y Rudensky. less Nature, 2010 Jan 15; 463(7282). PMID: 20072126 Free PMC article. Highly Cited.
Pharmacogenomic approach for the identification of novel determinants of acquired resistance to oxaliplatin in colorectal cancer. Anna Martinez-Cardús, Eva Martinez-Balibrea, +6 authors, Albert Abad. less Mol Cancer Ther, 2009 Jan 14; 8(1). PMID: 19139129
Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Rui Wang, Lina Kozhaya, +3 authors, Derya Unutmaz. less Proc Natl Acad Sci U S A, 2009 Aug 12; 106(32). PMID: 19666573 Free PMC article. Highly Cited.
B lymphocytes confer immune tolerance via cell surface GARP-TGF-β complex. Caroline H Wallace, Bill X Wu, +7 authors, Zihai Li. less JCI Insight, 2018 Apr 06; 3(7). PMID: 29618665 Free PMC article.
Protection from tumor necrosis factor-mediated cytolysis by platelets. C Philippe, B Philippe, +3 authors, B Fouqueray, J Perez, M Lebret, L Baud. less Am J Pathol, 1993 Dec 01; 143(6). PMID: 8256858 Free PMC article.
GP96 is a GARP chaperone and controls regulatory T cell functions. Yongliang Zhang, Bill X Wu, +9 authors, Zihai Li. less J Clin Invest, 2015 Jan 22; 125(2). PMID: 25607841 Free PMC article.
Decreased FOXP3+ and GARP+ Tregs to neoadjuvant chemotherapy associated with favorable prognosis in advanced gastric cancer. Kai Li, Fuchao Chen, Huijuan Xie. Onco Targets Ther, 2016 Jul 02; 9. PMID: 27366089 Free PMC article.
GARP: a key receptor controlling FOXP3 in human regulatory T cells. M Probst-Kepper, R Geffers, +16 authors, S Weiss. less J Cell Mol Med, 2009 May 21; 13(9B). PMID: 19453521 Free PMC article.
Prothrombin and its derivatives stimulate motility of melanoma cells. H Zhou, E C Gabazza, +4 authors, K Suzuki. less Thromb Haemost, 1998 Oct 06; 80(3). PMID: 9759619
Platelets and angiogenesis in malignancy. Ewa Sierko, Marek Z Wojtukiewicz. Semin Thromb Hemost, 2004 Mar 23; 30(1). PMID: 15034801 Review.
GARP as an Immune Regulatory Molecule in the Tumor Microenvironment of Glioblastoma Multiforme. Niklas Zimmer, Ella Kim, +6 authors, Andrea Tuettenberg. less Int J Mol Sci, 2019 Jul 31; 20(15). PMID: 31357555 Free PMC article.
Role of GARP in the activation of latent TGF-β1. Julie Stockis, Olivier Dedobbeleer, Sophie Lucas. Mol Biosyst, 2017 Aug 11; 13(10). PMID: 28795730 Review.
Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Myriam Labelle, Shahinoor Begum, Richard O Hynes. Cancer Cell, 2011 Nov 19; 20(5). PMID: 22094253 Free PMC article. Highly Cited.
Tumor-associated Macrophages (TAM) and Inflammation in Colorectal Cancer. Marco Erreni, Alberto Mantovani, Paola Allavena. Cancer Microenviron, 2011 Sep 13; 4(2). PMID: 21909876 Free PMC article. Highly Cited.
Deadly allies: the fatal interplay between platelets and metastasizing cancer cells. Luise Erpenbeck, Michael P Schön. Blood, 2010 Mar 03; 115(17). PMID: 20194899 Free PMC article. Review.
Translational regulation of inhibin βA by TGFβ via the RNA-binding protein hnRNP E1 enhances the invasiveness of epithelial-to-mesenchymal transitioned cells. B V Howley, G S Hussey, L A Link, P H Howe. Oncogene, 2015 Jun 23; 35(13). PMID: 26096938 Free PMC article.
Paraneoplastic thrombocytosis in ovarian cancer. Rebecca L Stone, Alpa M Nick, +31 authors, Anil K Sood. less N Engl J Med, 2012 Feb 18; 366(7). PMID: 22335738 Free PMC article. Highly Cited.
GARP Dampens Cancer Immunity by Sustaining Function and Accumulation of Regulatory T Cells in the Colon. Mohammad Salem, Caroline Wallace, +11 authors, Zihai Li. less Cancer Res, 2019 Jan 25; 79(6). PMID: 30674536 Free PMC article.
Involvement of platelets in tumour angiogenesis? H M Pinedo, H M Verheul, R J D'Amato, J Folkman. Lancet, 1998 Dec 16; 352(9142). PMID: 9848370
Transforming Growth Factor-β Signaling in Immunity and Cancer. Eduard Batlle, Joan Massagué. Immunity, 2019 Apr 18; 50(4). PMID: 30995507 Free PMC article. Highly Cited. Review.
GARP promotes the proliferation and therapeutic resistance of bone sarcoma cancer cells through the activation of TGF-β. Ana Belén Carrillo-Gálvez, Juan Esteban Quintero, +15 authors, Per Anderson. less Cell Death Dis, 2020 Nov 19; 11(11). PMID: 33203838 Free PMC article.
Platelets subvert T cell immunity against cancer via GARP-TGFβ axis. Saleh Rachidi, Alessandra Metelli, +11 authors, Zihai Li. less Sci Immunol, 2017 Aug 02; 2(11). PMID: 28763790 Free PMC article. Highly Cited.
Amplification of the BRCA2 pathway gene EMSY in sporadic breast cancer is related to negative outcome. Carmen Rodriguez, Luke Hughes-Davies, +5 authors, Charles Theillet. less Clin Cancer Res, 2004 Sep 10; 10(17). PMID: 15355907
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada. less J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981 Free PMC article. Highly Cited.
Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression. Rui Wang, Qi Wan, +2 authors, Lina Kozhaya, Hodaka Fujii, Derya Unutmaz. less PLoS One, 2008 Jul 17; 3(7). PMID: 18628982 Free PMC article.
TREM-1 ligand expression on platelets enhances neutrophil activation. Philipp Haselmayer, Ludger Grosse-Hovest, +2 authors, Markus P Radsak. less Blood, 2007 Apr 25; 110(3). PMID: 17452516
Perspectives on Regulatory T Cell Therapies. Michael Probst-Kepper, Andrea Kröger, Henk S P Garritsen, Jan Buer. Transfus Med Hemother, 2009 Jan 01; 36(5). PMID: 21076548 Free PMC article.
Platelets: signaling cells in the immune continuum. Andrew S Weyrich, Guy A Zimmerman. Trends Immunol, 2004 Aug 25; 25(9). PMID: 15324742 Review.
Monoclonal antibodies against GARP/TGF-β1 complexes inhibit the immunosuppressive activity of human regulatory T cells in vivo. Julia Cuende, Stéphanie Liénart, +15 authors, Sophie Lucas. less Sci Transl Med, 2015 Apr 24; 7(284). PMID: 25904740
GARP: a surface molecule of regulatory T cells that is involved in the regulatory function and TGF-β releasing. Liping Sun, Hao Jin, Hui Li. Oncotarget, 2016 Apr 21; 7(27). PMID: 27095576 Free PMC article. Review.
GARP (LRRC32) is essential for the surface expression of latent TGF-beta on platelets and activated FOXP3+ regulatory T cells. Dat Q Tran, John Andersson, +3 authors, Ethan M Shevach. less Proc Natl Acad Sci U S A, 2009 Aug 05; 106(32). PMID: 19651619 Free PMC article. Highly Cited.
Garp as a therapeutic target for modulation of T regulatory cell function. Ethan M Shevach. Expert Opin Ther Targets, 2016 Dec 22; 21(2). PMID: 28001437 Review.
CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. Zhi-Zhang Yang, Anne J Novak, +2 authors, Steven C Ziesmer, Thomas E Witzig, Stephen M Ansell. less Blood, 2007 Jul 07; 110(7). PMID: 17615291 Free PMC article.
Intracellular and extracellular TGF-β signaling in cancer: some recent topics. Kohei Miyazono, Yoko Katsuno, +2 authors, Daizo Koinuma, Shogo Ehata, Masato Morikawa. less Front Med, 2018 Jul 26; 12(4). PMID: 30043220 Highly Cited. Review.
How Soluble GARP Enhances TGFβ Activation. Sven Fridrich, Susanne A Hahn, +5 authors, Walter Stöcker. less PLoS One, 2016 Apr 08; 11(4). PMID: 27054568 Free PMC article.
Membrane protein GARP is a receptor for latent TGF-beta on the surface of activated human Treg. Julie Stockis, Didier Colau, Pierre G Coulie, Sophie Lucas. Eur J Immunol, 2009 Sep 15; 39(12). PMID: 19750484
Mesenchymal stromal cells express GARP/LRRC32 on their surface: effects on their biology and immunomodulatory capacity. Ana Belén Carrillo-Galvez, Marién Cobo, +9 authors, Per Anderson. less Stem Cells, 2014 Sep 04; 33(1). PMID: 25182959 Free PMC article.
Structural basis of latent TGF-β1 presentation and activation by GARP on human regulatory T cells. Stéphanie Liénart, Romain Merceron, +9 authors, Sophie Lucas. less Science, 2018 Oct 27; 362(6417). PMID: 30361387
miR-142-3p is involved in CD25+ CD4 T cell proliferation by targeting the expression of glycoprotein A repetitions predominant. Qihui Zhou, Sonja Haupt, +5 authors, Alla Skapenko. less J Immunol, 2013 May 08; 190(12). PMID: 23650616
Platelet-Derived GARP Induces Peripheral Regulatory T Cells-Potential Impact on T Cell Suppression in Patients with Melanoma-Associated Thrombocytosis. Niklas Zimmer, Franziska K Krebs, +6 authors, Andrea Tuettenberg. less Cancers (Basel), 2020 Dec 10; 12(12). PMID: 33291452 Free PMC article.
Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer. Alessandra Metelli, Bill X Wu, +10 authors, Zihai Li. less Cancer Res, 2016 Dec 04; 76(24). PMID: 27913437 Free PMC article.
Release of active TGF-β1 from the latent TGF-β1/GARP complex on T regulatory cells is mediated by integrin β8. Justin P Edwards, Angela M Thornton, Ethan M Shevach. J Immunol, 2014 Aug 17; 193(6). PMID: 25127859 Free PMC article.
Mesenchymal stroma/stem-like cells of GARP knockdown inhibits cell proliferation and invasion of mouse colon cancer cells (MC38) through exosomes. Haizhou Xing, Chunyan Liang, +3 authors, Xintong Xu, Hui Sun, Xiaojun Ma, Zhongxing Jiang. less J Cell Mol Med, 2020 Nov 07; 24(23). PMID: 33155413 Free PMC article.
Toward understanding the genetics of regulatory T cells in ovarian cancer. Melissa S Derycke, Bridget Charbonneau, +4 authors, Ellen L Goode. less Oncoimmunology, 2013 Jul 31; 2(6). PMID: 23894717 Free PMC article.
A key role of GARP in the immune suppressive tumor microenvironment. Susanne A Hahn, Annemarie Neuhoff, +12 authors, Andrea Tuettenberg. less Oncotarget, 2016 Jun 02; 7(28). PMID: 27248166 Free PMC article.
Hepatic Stellate Cells Inhibit T Cells through Active TGF-β1 from a Cell Surface-Bound Latent TGF-β1/GARP Complex. Yan Li, Byung-Gyu Kim, +4 authors, Feng Lin. less J Immunol, 2015 Aug 08; 195(6). PMID: 26246140 Free PMC article.
A critical function for TGF-beta signaling in the development of natural CD4+CD25+Foxp3+ regulatory T cells. Yongzhong Liu, Pin Zhang, +3 authors, Wanjun Chen. less Nat Immunol, 2008 Apr 29; 9(6). PMID: 18438410 Highly Cited.
TGF-β: an emerging player in drug resistance. Diede Brunen, Stefan M Willems, +3 authors, René Bernards. less Cell Cycle, 2013 Aug 27; 12(18). PMID: 23974105 Free PMC article.

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