uPAR is highly expressed in recurrent glioblastoma and represents a candidate CAR T cell target
Menée notamment à l'aide d'échantillons de glioblastomes d'origine humaine et de xénogreffes sur des modèles murins, cette étude démontre que le récepteur membranaire de l'activateur du plasminogène de type urokinase (uPAR) est fortement exprimé dans les tumeurs récidivantes puis met en évidence le rôle biologique de ce récepteur dans la tumorigenèse et démontre l'intérêt thérapeutique de lymphocytes CAR-T exprimant un antigène chimérique ciblant uPAR
Glioblastoma (GBM) comprises nearly 15% of primary central nervous system (CNS) tumors and 50% of malignant primary CNS tumors worldwide. Considerable tumoral heterogeneity exists in GBM, leading to inefficacy of current treatments and the absence of meaningful improvements in frontline therapies in the past 20 years. Through multiomic analysis of patient-derived primary and recurrent GBM cell lines, we identified the urokinase plasminogen activator receptor (uPAR) as a protumorigenic marker of putative brain tumor–initiating cells and a potential therapeutic target. We found that genetic disruption of uPAR expression impaired protumorigenic characteristics in vitro and in vivo, highlighting its biological role in tumorigenesis. We then generated uPAR-specific chimeric antigen receptor (CAR) T cells, which demonstrated potent antitumor activity in recurrent GBM patient–derived xenograft models. In addition to direct tumor cell killing, we found that uPAR is expressed on GBM-associated macrophages, enabling uPAR CAR T cells to target both GBM itself and cells in the tumor microenvironment. Together, these data illustrate the potency and therapeutic potential of targeting uPAR in GBM. The urokinase receptor uPAR is highly expressed in recurrent glioblastoma and is targetable using anti-uPAR chimeric antigen receptor T cells. A major challenge with immunotherapies, including those for glioblastoma, is the limited number of tumor-specific targets for the immune system to focus on; other targets may be enriched on tumor cells, but they run the risk of on-target, off-tumor effects. Here, Maich et al. used a multiomic approach to identify urokinase plasminogen activator receptor (uPAR) as a protein that is highly expressed in glioblastoma, specifically on brain tumor–initiating cells. Deletion of uPAR impaired tumor growth in vitro and in vivo, suggesting that loss of this protein as an immune evasion strategy may come at a fitness cost. Last, the authors generated chimeric antigen receptor T cells specific for uPAR, showing that they not only killed tumor cells in murine models but could also deplete uPAR-expressing tumor-associated macrophages. Thus, this two-for-one approach both kills tumor cells and contributes to remodeling of the tumor microenvironment, making uPAR an attractive target for glioblastoma-directed immunotherapies. —Courtney Malo
Science Translational Medicine , résumé, 2026