免疫抑制
MAPK/ERK通路
胰腺癌
癌症研究
信号转导
生物
癌症
免疫学
医学
内科学
细胞生物学
作者
Chenlei Zheng,Junli Wang,Yu Zhou,Dengxia Yi,Rujia Zheng,Ya-Bo Xie,Xiaobao Wei,Jiangchao Wu,Hang Shen,Mao Ye,Bo Kong,Yun-Hua Liu,Pinglong Xu,Qi Zhang,Tingbo Liang
出处
期刊:Cell Reports
[Elsevier]
日期:2024-04-01
卷期号:43 (4): 114088-114088
标识
DOI:10.1016/j.celrep.2024.114088
摘要
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.
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