Targeting Wnt/β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicity

Chetan Pundkar; Ferrin Antony; Xuejia Kang; Amarjit Mishra; R Jayachandra Babu; Pengyu Chen; Feng Li; Amol Suryawanshi

doi:10.1016/j.heliyon.2023.e16688

Targeting Wnt/β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicity

Heliyon. 2023 May 30;9(6):e16688. doi: 10.1016/j.heliyon.2023.e16688. eCollection 2023 Jun.

Authors

Chetan Pundkar¹, Ferrin Antony¹, Xuejia Kang^{2

3}, Amarjit Mishra¹, R Jayachandra Babu², Pengyu Chen³, Feng Li², Amol Suryawanshi¹

Affiliations

¹ Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
² Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA.
³ Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, AL 36849, USA.

Abstract

The aberrant activation of Wnt/β-catenin signaling in tumor cells and immune cells in the tumor microenvironment (TME) promotes malignant transformation, metastasis, immune evasion, and resistance to cancer treatments. The increased Wnt ligand expression in TME activates β-catenin signaling in antigen (Ag)-presenting cells (APCs) and regulates anti-tumor immunity. Previously, we showed that activation of Wnt/β-catenin signaling in dendritic cells (DCs) promotes induction of regulatory T cell responses over anti-tumor CD4⁺ and CD8⁺ effector T cell responses and promotes tumor progression. In addition to DCs, tumor-associated macrophages (TAMs) also serve as APCs and regulate anti-tumor immunity. However, the role of β-catenin activation and its effect on TAM immunogenicity in TME is largely undefined. In this study, we investigated whether inhibiting β-catenin in TME-conditioned macrophages promotes immunogenicity. Using nanoparticle formulation of XAV939 (XAV-Np), a tankyrase inhibitor that promotes β-catenin degradation, we performed in vitro macrophage co-culture assays with melanoma cells (MC) or melanoma cell supernatants (MCS) to investigate the effect on macrophage immunogenicity. We show that XAV-Np-treatment of macrophages conditioned with MC or MCS significantly upregulates the cell surface expression of CD80 and CD86 and suppresses the expression of PD-L1 and CD206 compared to MC or MCS-conditioned macrophages treated with control nanoparticle (Con-Np). Further, XAV-Np-treated macrophages conditioned with MC or MCS significantly increased IL-6 and TNF-α production, with reduced IL-10 production compared to Con-Np-treated macrophages. Moreover, the co-culture of MC and XAV-Np-treated macrophages with T cells resulted in increased CD8⁺ T cell proliferation compared to Con-Np-treated macrophages. These data suggest that targeted β-catenin inhibition in TAMs represents a promising therapeutic approach to promote anti-tumor immunity.

Keywords: Anti-tumor immunity; Immune-tolerance; Immunogenicity; Nanoparticle; Tumor microenvironment; Tumor-associated macrophages; Wnt; XAV939; β-catenin.