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

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.

Keywords: Cancer; GARP; Immune tolerance; Platelets; TGF-β; Treg.

Fig. 1

Timeline of literature on the study of GARP. GARP literature can virtually be divided into three time windows; each emphasizes interests of the field in a specific aspect of GARP function: the first round (green) of research focused on the characterization of the gene and the protein structure; the second round (red) was dedicated to studying the GARP function on Treg cells and tolerance; research during the latest period (light blue) analyzes GARP expression and function on platelets and cancer. The most pioneristic articles are indicated

Fig. 2

Structure of the membrane-bound GARP-latent TGF-β1 complex. GARP protein is structurally divided into three domains based on its primary sequence: the extracellular domain, the transmembrane domain, and the intracellular domain. The extracellular domain contains two sets of ten LRRs divided by a proline-rich domain and one C-terminal LRR (LRRCT). Two conserved Cys residues (Cys-192 and Cys-331) are located on the 7th and 12th LRR, respectively, and are responsible for two disulfide bond formation between GARP and Cys-4 of LAP of latent TGF-β

Fig. 3

GARP functions in TGF-β maturation and activation. TGF-β is synthetized as an inactive homodimeric pro-protein that is cleaved by a furin-like protease to yield the formation of latent TGF-β. GARP enhances furin-dependent cleavage and associates with latent TGF-β. The master chaperone gp96 in the lumen of the endoplasmic reticulum (ER, not depicted) ensures the proper folding of GARP and its surface expression. On the cell surface, GARP/latent TGF-β complex associates with alpha-beta integrins (αVβ6 and αVβ8) to release the mature TGF-β peptide. Mature TGF-β interacts with TGF-β receptors on the cell surface in both an autocrine and paracrine fashion. In some cases, GARP/latent TGF-β complex can also be released from the cell surface, but how TGF-β is activated from the soluble complex is not clear