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

• Published in: Cell reports (Cambridge) Vol. 43; no. 4; p. 114088
• Main Authors: Zheng, Chenlei, Wang, Junli, Zhou, Yu, Duan, Yi, Zheng, Rujia, Xie, Yuting, Wei, Xiaobao, Wu, Jiangchao, Shen, Hang, Ye, Mao, Kong, Bo, Liu, Yunhua, Xu, Pinglong, Zhang, Qi, Liang, Tingbo
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.04.2024; Elsevier
• Subjects: Animals; Antigens, CD - metabolism; Bone Marrow Stromal Antigen 2; Carcinoma, Pancreatic Ductal - immunology; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line, Tumor; cGAS-STING; CP: Cancer; CP: Immunology; CXCL7; Female; GPI-Linked Proteins - metabolism; Humans; Immune Tolerance; Interferon-alpha - metabolism; Mice; Mice, Inbred C57BL; pancreatic ductal adenocarcinoma; Pancreatic Neoplasms - immunology; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Signal Transduction; Tumor Microenvironment - immunology; tumor-associated macrophage; Tumor-Associated Macrophages - immunology; Tumor-Associated Macrophages - metabolism; Tumor-Associated Macrophages - pathology; CXCL7; CP: Immunology; bone marrow stromal antigen 2; CP: Cancer; tumor-associated macrophage; cGAS-STING; pancreatic ductal adenocarcinoma
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114088

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. [Display omitted] •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.