GPNMB is a transmembrane glycoprotein and melanin-producing enzyme, also known as hematopoietic growth factor-induced neurokinin type 1. As an immunosuppressive molecule, GPNMB promotes immune evasion and tumor progression by modulating innate and adaptive immune responses in the tumor microenvironment. Therapeutic strategies targeting GPNMB (such as antibody-drug conjugates and immunomodulators) may provide new therapeutic approaches to overcome immunotherapy resistance.
Expression distribution of GPNMB
GPNMB is primarily expressed in melanocytes, Hobart cells, fibroblasts, cardiomyocytes, basal keratinocytes, macrophages, and suprabasal keratinocytes. It is also expressed in microglia in the central nervous system (CNS) and in MΦs, DCs, and MDSCs in the immune system. Among leukocytes, GPNMB is primarily expressed by CD14+ monocytes and epidermal LCs (a type of immature DC).
(Data source: unprot)
The structure of GPNMB and its receptor
GPNMB is a type I transmembrane protein composed of 572 amino acids, which can produce two isoforms through alternative splicing.
The extracellular region: It contains the integrin recognition motif RGD (arginine-glycine-aspartic acid), which mediates integrin binding and participates in cell adhesion. The PKD domain is a polycystic kidney disease domain whose function is not fully understood, but may be involved in protein-protein interactions. It contains a hydrolysis site that can be cleaved by enzymes such as ADAM10 protease, producing a soluble extracellular segment (sGPNMB), which also exhibits biological activity.
Transmembrane region: anchored in the cell membrane.
Intracellular region: shorter, contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), which plays a key role in transmitting immunosuppressive signals.
（Data source AlphaFold）
GPNMB in immune regulation
GPNMB has diverse functions in the immune system and plays an important role in regulating inflammatory responses. GPNMB regulates both innate and adaptive immunity through its dual effects of inhibiting proinflammatory responses while promoting the recruitment and polarization of immunosuppressive cells.
GPNMB promotes macrophage polarization to an M2 phenotype, characterized by increased expression/secretion of anti-inflammatory immune mediators and decreased expression/secretion of pro-inflammatory immune mediators. GPNMB also induces dendritic cells to develop a tolerogenic phenotype, characterized by decreased expression/secretion of pro-inflammatory immune mediators. This ultimately leads to the formation of an immunosuppressive tumor microenvironment.
GPNMB regulates adaptive immunity by suppressing T cell responses. GPNMB inhibits T cell activation, proliferation, and infiltration. The PKD domain of GPNMB can inhibit T cell activation and proliferation by binding to polysulfated heparan glycosaminoglycans expressed on the surface of activated T cells. This leads to the recruitment of cognate proteins and CD148 protein tyrosine phosphatase, ultimately resulting in reduced T cell activation, proliferation, and effector function. GPNMB inhibits T cell infiltration, and soluble GPNMB (sGPNMB) leads to systemic immunosuppression by impairing T cell migration across the endothelium and excluding them from premetastatic niches (PMNs) in the lungs.
(Data source: Lazaratos AM, et al. Oncogene. 2022)
Targeted therapy for GPNMB
Glembatumumab is a monoclonal antibody targeting GPNMB, developed by Celldex Therapeutics for the treatment of metastatic melanoma.
Glembatumumab vedotin (GV) is an antibody-drug conjugate (ADC) consisting of a fully human IgG2 anti-GPNMB monoclonal antibody linked to the anti-cancer agent monomethylaureastatin E (MMAE). Combining GV with immunomodulatory agents may effectively enhance T cell function and immune-mediated tumor cell killing, potentially providing a new treatment option for immunogenic cancers.
(Data source: Lazaratos AM, et al. Oncogene. 2022)
