Glycoprotein-A repetitions predominant (GARP)–integrin alpha-V beta-8 complex (GARP–integrin αVβ8 complex)

The GARP–integrin alpha-V beta-8 interface is a critical molecular complex that regulates the activation of Transforming Growth Factor-beta 1 (TGF-β1) on the surface of regulatory T cells (Tregs) and platelets [1, 2]. GARP (Glycoprotein-A Repetitions Predominant, also known as LRRC32) acts as a transmembrane docking receptor that anchors the latent form of TGF-β1 to the cell membrane [1, 6]. Activation occurs when integrin alpha-V beta-8 (αVβ8) binds to the RGD motif within the latency-associated peptide (LAP) of the complex, facilitating the release of mature, active TGF-β1 through mechanical force or proteolytic recruitment [4, 8]. This localized activation is a key mechanism of immunosuppression in the tumor microenvironment, where active TGF-β1 inhibits the effector functions of CD8+ T cells and natural killer cells [1, 11]. Therapeutic agents like livmoniplimab (ABBV-151) are designed to bind the GARP-TGF-β1 complex and block its interaction with integrins, thereby preventing the generation of active TGF-β1 [18, 20]. By disrupting this interface, these drugs aim to reverse Treg-mediated immune evasion and enhance the efficacy of concurrent immunotherapies, such as PD-1/PD-L1 inhibitors, in patients with advanced solid tumors [10, 21]. Safety considerations for targeting this pathway include potential autoimmune reactions and effects on platelet function, given the expression of GARP on megakaryocytes [29, 34].

Other names

LRRC32GARPIntegrin alpha-V beta-8ITGAV/ITGB8GARP-TGF-beta complexGARP-LAP complexLeucine-rich repeat-containing protein 32

Inhibition of the mechanical release of active TGF-beta 1 from the GARP-anchored latent complex by blocking the integrin-binding interface.