DC-HIL/Glycoprotein Nmb Promotes Growth of Melanoma in Mice by Inhibiting the Activation of Tumor-Reactive T Cells

Abstract

DC-HIL/glycoprotein nmb (Gpnmb) expressed on antigen-presenting cells attenuates T-cell activation by binding to syndecan-4 (SD-4) on activated T cells. Because DC-HIL/Gpnmb is expressed abundantly by mouse and human melanoma lines, we posited that melanoma-associated DC-HIL/Gpnmb exerts similar inhibitory function on melanoma-reactive T cells. We generated small interfering RNA-transfected B16F10 melanoma cells to completely knock down DC-HIL/Gpnmb expression, with no alteration in cell morphology, melanin synthesis, or MHC class I expression. This knockdown had no effect on B16F10 proliferation in vitro or entry into the cell cycle following growth stimulation, but it markedly reduced the growth of these cells in vivo following their s.c. injection into syngeneic immunocompetent (but not immunodeficient) mice. This reduction in tumor growth was due most likely to an augmented capacity of DC-HIL-knocked down B16F10 cells (compared with controls) to activate melanoma-reactive T cells as documented in vitro and in mice. Whereas DC-HIL knockdown had no effect on susceptibility of melanoma to killing by cytotoxic T cells, blocking SD-4 function enhanced the reactivity of CD8 + T cells to melanoma-associated antigens on parental B16F10 cells.Using an assay examining the spread to the lung following i.v. injection, DC-HIL-knocked down cells produced lung foci at similar numbers compared with that produced by control cells, but the size of the former foci was significantly smaller than the latter. We conclude that DC-HIL/Gpnmb confers upon melanoma the ability to downregulate the activation of melanoma-reactive T cells, thereby allowing melanoma to evade immunologic recognition and destruction. As such, the DC-HIL/SD-4 pathway is a potentially useful target for antimelanoma immunotherapy. Cancer Res; 70(14); 5778-87. ©2010 AACR.

The role of the melanoma gene MC1R in Parkinson disease and REM sleep behavior disorder

“…(Paisan-Ruiz and Houlden, 2010) Another intriguing locus that was identified in PD GWAS is around the GPNMB gene,(Nalls, et al, 2014) which codes for the glycoprotein non-metastatic melanoma protein B, which may have an important role in melanoma. (Maric, et al, 2013,Tomihari, et al, 2010) Additional studies are needed to determine if these genes may contribute to the co-occurrence of PD and melanoma. In the current study, data on melanoma occurrence in the PD and RBD cohorts were not available.…”

Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

“…This observation led to the hypothesis that GPNMB may exert an inhibitory function on T-cell activation to promote tumor growth. Hence, GPNMB may impair melanoma-reactive T-cell activation, thereby allowing cancer cells to evade immunologic recognition and destruction [40]. This is, however, only one of the many mechanisms through which GPNMB exerts its pro-tumorigenic properties.…”

MAPK Pathway Inhibitors Sensitize BRAF-Mutant Melanoma to an Antibody-Drug Conjugate Targeting GPNMB

“…It forms a heterodimer with EGFR to facilitate HB-EGF mediated signals that stabilize HIF-1α expression, under normoxic conditions, to promote glycolytic reprogramming and tumorigenesis (18). In melanoma, GPNMB is also required for tumor growth and metastasis, and drives tumor progression via its immunomodulatory and immune suppressive effects (19). We show that GPNMB is elevated in melanoma biopsies from patients receiving BRAF and/or MEK inhibitors and demonstrate that combining BRAF and/or MEK inhibitors with Glembatumumab vedotin (CDX-011), an antibody drug conjugate that targets GPNMB, impairs MAPKi mediated pigmentation, and effectively controls the growth of melanoma.…”