TMIC-109. Wnt Inhibition Improves the Efficacy of Anti-Pd-1 Therapy in Glioblastoma

Immune checkpoint blockade therapy, including anti-PD-1 antibody (αPD1), has shown limited success in glioblastoma (GBM), a lethal brain tumor with a median survival of under two years. The Wnt signaling pathway - known for its role in development - can limit treatment outcomes in several malignancies, including GBM. Moreover, it plays a critical role in GBM progression by promoting stemness and epithelial-mesenchymal transition. While the preclinical evidence indicates that Wnt signaling is linked to anti-PD-1 (αPD1) resistance in extracranial tumors, its role in GBM immune suppression and αPD1 resistance remains unknown. Here, we show that Wnt7b is upregulated in GBM patients and contributes to αPD1 therapy resistance in a clinically relevant, stemness-rich murine GBM syngeneic model (GSC005). We observed that elevated Wnt7b and β-catenin levels correlated with a poor αPD1 response. We hypothesized that inhibiting Wnt signaling could sensitize tumors to αPD1 therapy by reprogramming the TME from immunosuppressive to immunostimulatory and bolster anti-tumor immunity. We orthotopically implanted GSC005 into immunocompetent mice, then tracked tumor growth using ultrasound, and analyzed tumor and immune cell subpopulations by flow cytometry. Combining the porcupine inhibitor WNT974 with αPD1 improved median survival from 25 to 59 Days (p < 0.05), with 25% of mice achieving long-term survival. WNT974 with αPD1 increased DC3-like dendritic cells and reduced granulocytic myeloid-derived suppressor cells (gMDSCs). Moreover, this combination increased the Ki67+ CD8 T/Ki67+ Treg ratio, shifting the balance towards an anti-tumor immune response and upregulated Gzmb in CD8 T cells, enhancing their effector function. Interestingly, resistance to WNT974 + αPD1 was marked by elevated monocytic MDSCs, pERK/MAPK pathway activation, and modest T cell exhaustion. Our study provides compelling data and rationale to repurpose WNT974, reported to be safe in a Phase I trial in extracranial cancer patients, in combination with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling.