STEM-04. PD-1 INDEPENDENT OF PD-L1 LIGATION PROMOTES GLIOBLASTOMA GROWTH THROUGH THE NFkB PATHWAY

Abstract

Abstract Brain tumor-initiating cells (BTICs) drive glioblastoma growth through not fully understood mechanisms. Here, we found that a proportion of human and murine BTICs expressed programmed cell death protein (PD-1). Gain- or loss-of-function studies revealed that tumor-intrinsic PD-1 promoted proliferation, and self-renewal of BTICs. Mechanistically, site-directed mutagenesis, RNA sequencing and pharmacological inhibitors implicated SHP-2-mediated activation of NFkB downstream of PD-1 in BTICs. Notably, the tumor-intrinsic promoting effects of PD-1 did not require PD-L1 ligation; thus, the therapeutic blocking antibodies inhibiting PD-1/PD-L1 interaction which failed in glioblastoma trials could not overcome the growth advantage of PD-1 in BTICs. Finally, mice with intracranial Pdcd1 over- or underexpressing BTICs had shorter or longer survival, respectively, 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 non-immune resistance mechanism of GBM patients to PD-1 or PD-L1 blocking therapies.