Targeting Wnt signaling for improved glioma immunotherapy

Area of Science:

• Neuro-oncology
• Cancer Immunology
• Molecular Biology

Background:

• Glioblastoma (GBM) is an aggressive brain cancer with poor prognosis despite standard treatments.
• Wnt/β-catenin signaling activation in GBM correlates with poor outcomes and promotes glioma stem-like cell proliferation.
• Current immunotherapies show limited efficacy in GBM due to tumor heterogeneity and antigen escape.

Purpose of the Study:

• To investigate the effects of the Wnt/CBP/β-catenin antagonist ICG-001 on glioma cells and the tumor microenvironment (TME).
• To assess ICG-001's impact on immune cell infiltration, vascularization, and metabolic changes in GBM.
• To evaluate ICG-001's potential to enhance chimeric antigen receptor (CAR) T cell therapy for glioblastoma.

Main Methods:

• Utilized patient-derived xenografts and murine glioma models (GL261, K-Luc).
• Administered ICG-001 to assess its effects on glioma cell proliferation, differentiation, and gene expression (e.g., Survivin/BIRC5).
• Analyzed immune cell infiltration (CD3+, CD8+), vascular markers (CD31), and gene expression in response to ICG-001, alone and in combination with CAR T cells.

Main Results:

• ICG-001 demonstrated in vitro cytostatic effects and induced differentiation in glioma cells.
• Treatment with ICG-001 downregulated the Wnt/CBP/β-catenin target gene Survivin/BIRC5.
• ICG-001 enhanced CD3+ and CD8+ T cell infiltration and CD31 expression in a syngeneic glioma model.
• Pre-treatment with ICG-001 followed by CAR T cell therapy showed improved immune cell infiltration compared to single treatments.

Conclusions:

• Specific Wnt/CBP/β-catenin antagonism with ICG-001 induces glioma stem cell differentiation and modulates the tumor microenvironment.
• ICG-001 promotes immune cell activation and recruitment, suggesting a role in overcoming GBM resistance.
• ICG-001 holds promise as an adjunct therapy to enhance the efficacy of immunotherapy in glioblastoma patients.