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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Published in | Cell reports (Cambridge) Vol. 43; no. 4; p. 114088 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
23.04.2024
Elsevier |
Subjects | |
Online Access | Get full text |
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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.
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•IFNα-induced BST2+ macrophages were highly expressed in PDAC and had a poor prognosis•BST2+ macrophages drive CD8+ T cell exhaustion through the ERK-CXCL7 pathway•PD-L1-CXCL7 antibody combination enhances anti-tumor efficacy in BST2+ macrophage tumors•PDAC mtDNA damage activates cGAS-STING-IFNα within macrophages, inducing BST2 expression
Zheng et al. uncover that mtDNA damage in PDAC triggers the cGAS-STING-IFNα pathway. Therefore, IFNα-induced BST2+ macrophages drive CD8+ T cell exhaustion and pancreatic tumor growth via the ERK-CXCL7-CXCR2/AKT/mTOR pathway. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2211-1247 2211-1247 |
DOI: | 10.1016/j.celrep.2024.114088 |