Browsing by Author "Mahoney, Douglas J."

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    PD-1 independent of PD-L1 ligation promotes glioblastoma growth through the NFκB pathway
    (American Association for the Advancement of Science, 2021-11-05) Mirzaei, Reza; Gordon, Ashley; Zemp, Franz J.; Kumar, Mehul; Sarkar, Susobhan; Luchman, H. Artee; Bellail, Anita C.; Hao, Chunhai; Mahoney, Douglas J.; Dunn, Jeff F.; Bose, Pinaki; Yong, V. Wee; Pathology and Laboratory Medicine, School of Medicine
    Brain 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.