Blocking Wnt/β-catenin Signal Amplifies Anti-PD-1 Therapeutic Efficacy by Inhibiting Tumor Growth, Migration, and Promoting Immune Infiltration in Glioblastomas

Abstract

Glioblastoma (GBM), as the immunologically cold tumor, respond poorly to programmed cell death 1 (PD-1) immune checkpoint inhibitors because of insufficient immune infiltration. Herein, through the analysis of The Cancer Genome Atlas data and clinical glioma samples, we found Wnt/β-catenin signal was activated in GBM and inversely related to the degree of immune cell (CD8⁺) infiltration and programmed cell death ligand 1 (PD-L1) expression. Blockade of Wnt/β-catenin signal could inhibit GBM U118 cells' growth and migration, and upregulate their PD-L1 expression which indicated the possible better response to anti-PD-1 immunotherapy. Besides, in a co-culture system comprising U118 cells and Jurkat cells, Wnt inhibition alleviated Jurkat cell's apoptosis and enhanced its cytotoxic function as evidenced by obviously increased effector cytokine IFNγ secretion and lactate dehydrogenase release. Moreover, the enhanced anti-GBM effect of PD-1 antibody triggered by Wnt inhibition was observed in GL261 homograft mouse model, and the upregulation of immune cell (CD4⁺/CD8⁺) infiltration and IFNγ secretion in tumor tissues suggested that Wnt/β-catenin inhibition could inflame cold tumor and then sensitize GBM to PD-1 blockade therapy. Taken together, our study verified the blockade of Wnt/β-catenin signal could augment the efficacy of PD-1 blockade therapy on GBM through directly inhibiting tumor proliferation and migration, as well as facilitating T-cell infiltration and PD-L1 expression in tumor microenvironment.