Mirzaei, RezaGordon, AshleyZemp, Franz J.Kumar, MehulSarkar, SusobhanLuchman, H. ArteeBellail, Anita C.Hao, ChunhaiMahoney, Douglas J.Dunn, Jeff F.Bose, PinakiYong, V. Wee2023-04-052023-04-052021-11-05Mirzaei R, Gordon A, Zemp FJ, et al. PD-1 independent of PD-L1 ligation promotes glioblastoma growth through the NFκB pathway. Sci Adv. 2021;7(45):eabh2148. doi:10.1126/sciadv.abh2148https://hdl.handle.net/1805/32241Brain tumor–initiating cells (BTICs) drive glioblastoma growth through not fully understood mechanisms. Here, we found that about 8% of cells within the human glioblastoma microenvironment coexpress programmed cell death 1 (PD-1) and BTIC marker. Gain- or loss-of-function studies revealed that tumor-intrinsic PD-1 promoted proliferation and self-renewal of BTICs. Phosphorylation of tyrosines within the cytoplasmic tail of PD-1 recruited Src homology 2–containing phosphatase 2 and activated the nuclear factor kB in BTICs. Notably, the tumor-intrinsic promoting effects of PD-1 did not require programmed cell death ligand 1(PD-L1) ligation; thus, the therapeutic antibodies inhibiting PD-1/PD-L1 interaction could not overcome the growth advantage of PD-1 in BTICs. Last, BTIC-intrinsic PD-1 accelerated intracranial tumor growth, and this occurred in mice lacking T and B cells. These findings point to a critical role for PD-1 in BTICs and uncover a nonimmune resistance mechanism of patients with glioblastoma to PD-1– or PD-L1–blocking therapies.en-USAttribution-NonCommercial 4.0 InternationalBrain tumor–initiating cellsGlioblastoma growthTyrosinesPhosphorylationArticle