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

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

  • Cell Rep. 2024 Apr 23;43(4):114088. doi: 10.1016/j.celrep.2024.114088.
Chenlei Zheng 1 Junli Wang 1 Yu Zhou 2 Yi Duan 1 Rujia Zheng 2 Yuting Xie 1 Xiaobao Wei 1 Jiangchao Wu 1 Hang Shen 1 Mao Ye 1 Bo Kong 3 Yunhua Liu 4 Pinglong Xu 5 Qi Zhang 6 Tingbo Liang 7
Affiliations

Affiliations

  • 1 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • 2 Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
  • 3 Department of General, Visceral and Transplantation Surgery, Section of Surgical Research, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  • 4 Department of Pathology & Pathophysiology, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 5 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; The MOE Key Laboratory of Biosystems Homeostasis & Protection and Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • 6 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou 310003, China; Zhejiang University Cancer Center, Hangzhou 310003, China; MOE Joint International Research Laboratory of Pancreatic Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address: qi.zhang@zju.edu.cn.
  • 7 Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Provincial Key Laboratory of Pancreatic Disease, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Zhejiang Clinical Research Center of Hepatobiliary and Pancreatic Diseases, Hangzhou 310003, China; The Innovation Center for the Study of Pancreatic Diseases of Zhejiang Province, Hangzhou 310003, China; Zhejiang University Cancer Center, Hangzhou 310003, China; MOE Joint International Research Laboratory of Pancreatic Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address: liangtingbo@zju.edu.cn.
Abstract

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.

Keywords

CP: Cancer; CP: Immunology; CXCL7; bone marrow stromal antigen 2; cGAS-STING; pancreatic ductal adenocarcinoma; tumor-associated macrophage.

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