Project 2: Restore Myeloid Phagocytosis in Glioblastoma by Targeting the QKI/PPARb/RXRa Complex

SUMMARY: PROJECT 2 Immunotherapies, including immune checkpoint blockades, have not benefited patients with glioblastoma (GBM), largely due to abundant immune-suppressive GBM-associated microglia/macrophages (GAMs), which can comprise up to ~30% of the tumor mass. A major gap in our current knowledge is how to reverse therapeutically the immunosuppressive features of GAMs. Although heterogeneous, GAMs almost ubiquitously exhibit pro-tumorigenic states with defective phagocytosis. We reasoned that restoration of phagocytosis in GAMs would promote anti-tumor activity by enhancing their ability to digest and process glioma cells and present tumor specific antigens to activate the adaptive immune system. By analyzing human and mouse GBM samples by single cell RNA sequencing, we found that suppression of Quaking (QKI) is a universal feature in human and mouse GAMs and contributes to the impairment of the phagocytic activity of GAMs. QKI forms a complex with peroxisome proliferator-activated receptor β (PPARβ) and retinoid X receptor α (RXRα), called QPR, which regulates unsaturated fatty acids (UFAs) synthesis, influencing membrane fluidity and driving phagocytosis. Conditional knockout of Qki or PPARβ in GAMs greatly impairs the phagocytosis of GAMs and enhances gliomagenesis by decreasing immune cell infiltration. Conversely, activating QPR through small molecule agonists of PPARβ (KD3010) or RXRα (bexarotene) greatly enhances the phagocytic ability of GAMs and suppresses GBM growth in syngeneic glioma mouse models, demonstrating the therapeutic potential of these agents. Based on the above evidence, we hypothesize that activating QPR with small molecular agonists will restore GAM phagocytosis, normalize the defective immune microenvironment of GBM and consequently halt GBM progression. To test this hypothesis, we will: Decipher the molecular mechanisms underlying the effect of QPR activators on phagocytic activity in GAMs in vitro (Aim 1); Investigate the molecular and cellular effects of KD3010/bexarotene on GAMs in pre-clinical in vivo animal models (Aim 2); And perform a window-of-opportunity clinical trial to evaluate the therapeutic potential of bexarotene in patients with recurrent GBM (Aim 3). In all, these studies will define QPR agonists as a new class of immunotherapeutics that can provide new hope for curing GBM by overcoming the immunosuppressive tumor microenvironment that drives this dreaded disease. .