Pundkar Chetan, Antony Ferrin, Kang Xuejia, Mishra Amarjit, Babu R Jayachandra, Chen Pengyu, Li Feng, Suryawanshi Amol
Department of Pathobiology, College of Veterinary Medicine, Auburn University, Auburn, AL 36849, USA.
Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA.
Heliyon. 2023 May 30;9(6):e16688. doi: 10.1016/j.heliyon.2023.e16688. eCollection 2023 Jun.
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 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.
肿瘤微环境（TME）中肿瘤细胞和免疫细胞内Wnt/β-连环蛋白信号的异常激活会促进恶性转化、转移、免疫逃逸以及对癌症治疗的抵抗。TME中Wnt配体表达的增加会激活抗原呈递细胞（APC）中的β-连环蛋白信号，并调节抗肿瘤免疫。此前，我们发现树突状细胞（DC）中Wnt/β-连环蛋白信号的激活会促进调节性T细胞反应的诱导，而不是抗肿瘤CD4和CD8效应T细胞反应，并促进肿瘤进展。除DC外，肿瘤相关巨噬细胞（TAM）也作为APC发挥作用并调节抗肿瘤免疫。然而，β-连环蛋白激活在TME中的作用及其对TAM免疫原性的影响在很大程度上尚不清楚。在本研究中，我们调查了抑制TME条件下巨噬细胞中的β-连环蛋白是否会促进免疫原性。使用促进β-连环蛋白降解的端锚聚合酶抑制剂XAV939的纳米颗粒制剂（XAV-Np），我们进行了巨噬细胞与黑色素瘤细胞（MC）或黑色素瘤细胞上清液（MCS）的共培养试验，以研究对巨噬细胞免疫原性的影响。我们发现，与用对照纳米颗粒（Con-Np）处理的MC或MCS条件下的巨噬细胞相比，用XAV-Np处理MC或MCS条件下的巨噬细胞可显著上调CD80和CD86的细胞表面表达，并抑制PD-L1和CD206的表达。此外，与Con-Np处理的巨噬细胞相比，用XAV-Np处理MC或MCS条件下的巨噬细胞可显著增加IL-6和TNF-α的产生，同时减少IL-10的产生。此外，与Con-Np处理的巨噬细胞相比，MC与XAV-Np处理的巨噬细胞与T细胞的共培养导致CD8 T细胞增殖增加。这些数据表明，靶向抑制TAM中的β-连环蛋白是一种有前景的促进抗肿瘤免疫的治疗方法。
