Targeting Wnt/β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicity
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 antig...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-06-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844023038951 |
| _version_ | 1797812056395612160 |
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| author | Chetan Pundkar Ferrin Antony Xuejia Kang Amarjit Mishra R. Jayachandra Babu Pengyu Chen Feng Li Amol Suryawanshi |
| author_facet | Chetan Pundkar Ferrin Antony Xuejia Kang Amarjit Mishra R. Jayachandra Babu Pengyu Chen Feng Li Amol Suryawanshi |
| author_sort | Chetan Pundkar |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T07:32:56Z |
| format | Article |
| id | doaj.art-d0e476ae385048e2814172ef12023c24 |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-03-13T07:32:56Z |
| publishDate | 2023-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Heliyon |
| spelling | doaj.art-d0e476ae385048e2814172ef12023c242023-06-04T04:24:10ZengElsevierHeliyon2405-84402023-06-0196e16688Targeting Wnt/β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicityChetan Pundkar0Ferrin Antony1Xuejia Kang2Amarjit Mishra3R. Jayachandra Babu4Pengyu Chen5Feng Li6Amol Suryawanshi7Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USADepartment of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USADepartment of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA; Materials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, AL 36849, USADepartment of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USADepartment of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USAMaterials Research and Education Center, Materials Engineering, Department of Mechanical Engineering, Auburn University, Auburn, AL 36849, USADepartment of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USADepartment of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA; Corresponding author. 240B Greene Hall, Auburn, AL, 36849, USA.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.http://www.sciencedirect.com/science/article/pii/S2405844023038951Tumor microenvironmentβ-cateninXAV939NanoparticleWntTumor-associated macrophages |
| spellingShingle | Chetan Pundkar Ferrin Antony Xuejia Kang Amarjit Mishra R. Jayachandra Babu Pengyu Chen Feng Li Amol Suryawanshi Targeting Wnt/β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicity Heliyon Tumor microenvironment β-catenin XAV939 Nanoparticle Wnt Tumor-associated macrophages |
| title | Targeting Wnt/β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicity |
| title_full | Targeting Wnt/β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicity |
| title_fullStr | Targeting Wnt/β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicity |
| title_full_unstemmed | Targeting Wnt/β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicity |
| title_short | Targeting Wnt/β-catenin signaling using XAV939 nanoparticles in tumor microenvironment-conditioned macrophages promote immunogenicity |
| title_sort | targeting wnt β catenin signaling using xav939 nanoparticles in tumor microenvironment conditioned macrophages promote immunogenicity |
| topic | Tumor microenvironment β-catenin XAV939 Nanoparticle Wnt Tumor-associated macrophages |
| url | http://www.sciencedirect.com/science/article/pii/S2405844023038951 |
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