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IFNα-induced BST2+ tumor-associated macrophages facilitate immunosuppression and tumor growth in pancreatic cancer by ERK-CXCL7 signaling

Pancreatic ductal adenocarcinoma (PDAC) features an immunosuppressive tumor microenvironment (TME) that resists immunotherapy. Tumor-associated macrophages, abundant in the TME, modulate T cell responses. Bone marrow stromal antigen 2-positive (BST2+) macrophages increase in KrasG12D/+; Trp53R172H/+...

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Main Authors: Zheng, Chenlei (Author) , Wang, Junli (Author) , Zhou, Yu (Author) , Duan, Yi (Author) , Zheng, Rujia (Author) , Xie, Yuting (Author) , Wei, Xiaobao (Author) , Wu, Jiangchao (Author) , Shen, Hang (Author) , Ye, Mao (Author) , Kong, Bo (Author) , Liu, Yunhua (Author) , Xu, Pinglong (Author) , Zhang, Qi (Author) , Liang, Tingbo (Author)
Format: Article (Journal)
Language:English
Published: 23 April 2024
In: Cell reports
Year: 2024, Volume: 43, Issue: 4, Pages: 1-27
ISSN:2211-1247
DOI:10.1016/j.celrep.2024.114088
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.celrep.2024.114088
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2211124724004169
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Author Notes:Chenlei Zheng, Junli Wang, Yu Zhou, Yi Duan, Rujia Zheng, Yuting Xie, Xiaobao Wei, Jiangchao Wu, Hang Shen, Mao Ye, Bo Kong, Yunhua Liu, Pinglong Xu, Qi Zhang, and Tingbo Liang
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Summary:Pancreatic ductal adenocarcinoma (PDAC) features an immunosuppressive tumor microenvironment (TME) that resists immunotherapy. Tumor-associated macrophages, abundant in the TME, modulate T cell responses. Bone marrow stromal antigen 2-positive (BST2+) macrophages increase in KrasG12D/+; Trp53R172H/+; Pdx1-Cre mouse models during PDAC progression. However, their role in PDAC remains elusive. Our findings reveal a negative correlation between BST2+ macrophage levels and PDAC patient prognosis. Moreover, an increased ratio of exhausted CD8+ T cells is observed in tumors with up-regulated BST2+ macrophages. Mechanistically, BST2+ macrophages secrete CXCL7 through the ERK pathway and bind with CXCR2 to activate the AKT/mTOR pathway, promoting CD8+ T cell exhaustion. The combined blockade of CXCL7 and programmed death-ligand 1 successfully decelerates tumor growth. Additionally, cGAS-STING pathway activation in macrophages induces interferon (IFN)α synthesis leading to BST2 overexpression in the PDAC TME. This study provides insights into IFNα-induced BST2+ macrophages driving an immune-suppressive TME through ERK-CXCL7 signaling to regulate CD8+ T cell exhaustion in PDAC.
Item Description:Im Text ist "+" hochgestellt
Online verfügbar 10 April 2024, Version des Artikels 10 April 2024
Gesehen am 18.11.2024
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2024.114088

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