Abstract B015: Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma

Abstract Immune checkpoint blockers, including anti-PD-1 (αPD1), have failed in multiple phase III clinical trials in glioblastoma (GBM), a malignant brain tumor with a median survival of <2 years with current treatments. Wnt signaling plays a crucial role in multiple developmental processes and contributes to limited treatment outcomes of several malignancies, including GBM. Wnt signaling aids GBM progression by maintaining stemness, promoting epithelial-mesenchymal transition, and inducing chemoresistance. Preclinical evidence indicates that Wnt signaling may contribute to αPD1 resistance in extracranial tumors. However, its pertinence in the failure of αPD1 in GBM is unknown. In our study, we identified Wnt7b, upregulated in GBM patients, is a determinant of resistance to αPD1 therapy in a clinically relevant GBM murine model with abundant GSCs. Increased levels of Wnt7b and β-catenin correlated with resistance to αPD1 therapy. We hypothesized that Wnt inhibition could potentiate αPD1 therapy by reprogramming the immunosuppressive tumor microenvironment (TME) to an immune-stimulatory state. We orthotopically implanted a stem-rich syngeneic mouse GBM cell line, GSC005, into immunocompetent mice, then tracked tumor growth and analyzed tumor and immune cell subpopulations using Western blot, qPCR, and immunohistochemistry and flow cytometry. Combining a porcupine inhibitor (WNT974) with αPD1 therapy enhanced anti-tumor immune responses and extended the median survival of mice with orthotopic GBM from 25 to 59 days, with 25% cured. Furthermore, this combination reprogrammed the TME, increasing antigen-presenting DC3-like dendritic cells and reducing granulocytic myeloid-derived suppressor cells (gMDSCs). Moreover, it increased the Ki67+CD8/Ki67+Treg (regulatory T cell) ratio, shifting the CD8 balance towards an anti-tumor immune response. Interestingly, resistance to the combination therapy was associated with an increase in monocytic MDSCs (mMDSCs). Our preclinical findings provide compelling data and rationale to test 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. Citation Format: Shanmugarajan Krishnan, Somin Lee, Zohreh Amoozgar, Sonu Subudhi, Ashwin S. Kumar, Jessica Posada, Neal Lindeman, Pinji Lei, Mark Duquette, Peigen Huang, Patrik Andersson, Meenal Datta, Lance L. Munn, Dai Fukumura, Rakesh K. Jain. Wnt inhibition improves the efficacy of anti-PD-1 therapy in glioblastoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B015.