Clinical and functional profiling nominates melanoma as a priority indication for GPNMB CAR T cell therapy

ABSTRACT: Glycoprotein nonmetastatic melanoma protein B (GPNMB) has emerged as a tractable cancer target for engineered immune cell therapies, but the cancers best suited for GPNMB-directed cellular therapy remain uncertain. Here, we combined clinical profiling with functional testing to prioritize indications for GPNMB chimeric antigen receptor (CAR) T cell therapy. Immunohistochemical analysis of a multicancer cohort comprising tumors from 357 patients across 20 organ sites confirmed broad GPNMB expression but revealed substantial variation across cancer types and among patients within indications. Focused profiling of pancreatic and colorectal cancer cohorts demonstrated limited overall expression. To establish the functional relevance of GPNMB in heterogeneous solid tumors, we tested GPNMB CAR T cells in lung and thyroid cancer cell models with differing levels of GPNMB. GPNMB CAR T cell activity tracked with the abundance of cell-surface antigen. GPNMB-high models were efficiently eliminated, antigen-low models showed intermediate susceptibility, and antigen-negative models showed no antitumor activity. Melanoma profiling demonstrated the most favorable clinical expression profile. Analysis of 158 patients revealed frequent, high GPNMB expression across anatomically diverse primary tumors and metastatic specimens. Spatial transcriptomic analysis further corroborated that GPNMB was most frequently detected in malignant-cell-dominant regions. Consistent with this clinical profile, GPNMB CAR T cells demonstrated activity across a diverse panel of melanoma cell models. Together, these findings support GPNMB as a broadly relevant but variably expressed tumor antigen and nominate melanoma as a priority clinical entry point for GPNMB CAR T cell therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE346114 | GEO | 2026/09/08

REPOSITORIES: GEO