Targeting Wnt signaling for improved glioma immunotherapy.

Despite aggressive standard-of-care therapy, including surgery, radiation, and chemotherapy, glioblastoma recurrence is almost inevitable and uniformly lethal. Activation of glioma-intrinsic Wnt/β-catenin signaling is associated with a poor prognosis and the proliferation of glioma stem-like cells, leading to malignant transformation and tumor progression. Impressive results in a subset of cancers have been obtained using immunotherapies including anti-CTLA4, anti-PD-1, and anti-PD-L1 or chimeric antigen receptor (CAR) T cell therapies. However, the heterogeneity of tumors, low mutational burden, single antigen targeting, and associated antigen escape contribute to non-responsiveness and potential tumor recurrence despite these therapeutic efforts. In the current study, we determined the effects of the small molecule, highly specific Wnt/CBP (CREB Binding Protein)/β-catenin antagonist ICG-001, on glioma tumor cells and the tumor microenvironment (TME)-including its effect on immune cell infiltration, blood vessel decompression, and metabolic changes. Using multiple glioma patient-derived xenografts cell lines and murine tumors (GL261, K-Luc), we demonstrated In these glioma cell lines, we further demonstrated that ICG-001 downregulated the CBP/β-catenin target gene We conclude that specific Wnt/CBP/β-catenin antagonism results in pleotropic changes in the glioma TME, including glioma stem cell differentiation, modulation of the stroma, and immune cell activation and recruitment, thereby suggesting a possible role for enhancing immunotherapy in glioma patients.

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Copyright © 2024 Gutova, Hibbard, Ma, Natri, Adhikarla, Chimge, Qiu, Nguyen, Melendez, Aguilar, Starr, Yin, Rockne, Ono, Banovich, Yuan, Brown and Kahn.

Déclaration de conflit d'intérêts

MK is a cofounder and holds equity in 3 + 2 Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.