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血管活性肠肽阻断通过调节 CT26 荷瘤小鼠巨噬细胞极化和功能抑制肿瘤生长。

Vasoactive intestinal peptide blockade suppresses tumor growth by regulating macrophage polarization and function in CT26 tumor-bearing mice.

机构信息

Department of Pharmacology, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki, Kita, Kagawa, 761-0793, Japan.

Department of Biochemistry, Faculty of Medicine, Kagawa University, Kagawa, Japan.

出版信息

Sci Rep. 2023 Jan 17;13(1):927. doi: 10.1038/s41598-023-28073-6.

DOI:10.1038/s41598-023-28073-6
PMID:36650220
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9845384/
Abstract

Macrophages are a major population of immune cells in solid cancers, especially colorectal cancers. Tumor-associated macrophages (TAMs) are commonly divided into M1-like (tumor suppression) and M2-like (tumor promotion) phenotypes. Vasoactive intestinal peptide (VIP) is an immunoregulatory neuropeptide with a potent anti-inflammatory function. Inhibition of VIP signaling has been shown to increase CD8 T cell proliferation and function in viral infection and lymphoma. However, the role of VIP in macrophage polarization and function in solid tumors remains unknown. Here, we demonstrated that conditioned medium from CT26 (CT26-CM) cells enhanced M2-related marker and VIP receptor (VPAC) gene expression in RAW264.7 macrophages. VIP hybrid, a VIP antagonist, enhanced M1-related genes but reduced Mrc1 gene expression and increased phagocytic ability in CT26-CM-treated RAW264.7 cells. In immunodeficient SCID mice, VIP antagonist alone or in combination with anti-PD-1 antibody attenuated CT26 tumor growth compared with the control. Analysis of tumor-infiltrating leukocytes found that VIP antagonist increased M1/M2 ratios and macrophage phagocytosis of CT26-GFP cells. Furthermore, Vipr2 gene silencing or VPAC2 activation affected the polarization of CT26-CM-treated RAW264.7 cells. In conclusion, the inhibition of VIP signaling enhanced M1 macrophage polarization and macrophage phagocytic function, resulting in tumor regression in a CT26 colon cancer model.

摘要

巨噬细胞是实体瘤中主要的免疫细胞群体，尤其是结直肠癌。肿瘤相关巨噬细胞（TAMs）通常分为 M1 样（肿瘤抑制）和 M2 样（肿瘤促进）表型。血管活性肠肽（VIP）是一种具有强大抗炎功能的免疫调节神经肽。抑制 VIP 信号已被证明可增加病毒感染和淋巴瘤中 CD8+T 细胞的增殖和功能。然而，VIP 在实体瘤中巨噬细胞极化和功能中的作用尚不清楚。在这里，我们证明 CT26（CT26-CM）细胞的条件培养基增强了 RAW264.7 巨噬细胞中的 M2 相关标志物和 VIP 受体（VPAC）基因表达。VIP 混合，一种 VIP 拮抗剂，增强了 M1 相关基因，但降低了 Mrc1 基因表达，并增加了 CT26-CM 处理的 RAW264.7 细胞中的吞噬能力。在免疫缺陷 SCID 小鼠中，与对照组相比，VIP 拮抗剂单独或与抗 PD-1 抗体联合使用可减弱 CT26 肿瘤的生长。对肿瘤浸润白细胞的分析发现，VIP 拮抗剂增加了 M1/M2 比值和巨噬细胞对 CT26-GFP 细胞的吞噬作用。此外，Vipr2 基因沉默或 VPAC2 激活影响了 CT26-CM 处理的 RAW264.7 细胞的极化。总之，抑制 VIP 信号增强了 M1 巨噬细胞的极化和吞噬功能，导致 CT26 结肠癌模型中的肿瘤消退。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0701/9845384/19ef0c6f53d6/41598_2023_28073_Fig6_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0701/9845384/19ef0c6f53d6/41598_2023_28073_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0701/9845384/6cd454cca975/41598_2023_28073_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0701/9845384/4aac8417f4cf/41598_2023_28073_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0701/9845384/3304866089eb/41598_2023_28073_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0701/9845384/062f4584935b/41598_2023_28073_Fig4_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0701/9845384/19ef0c6f53d6/41598_2023_28073_Fig6_HTML.jpg

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