1. Academic Validation
  2. Loss of Annexin A1 in macrophages restrains efferocytosis and remodels immune microenvironment in pancreatic cancer by activating the cGAS/STING pathway

Loss of Annexin A1 in macrophages restrains efferocytosis and remodels immune microenvironment in pancreatic cancer by activating the cGAS/STING pathway

  • J Immunother Cancer. 2024 Sep 4;12(9):e009318. doi: 10.1136/jitc-2024-009318.
Zelin Hou # 1 2 Fengchun Lu # 1 Jiajing Lin # 1 Yuwei Wu 1 2 Linjin Chen 1 Haizong Fang 1 Linlin Chen 3 Shihan Zhang 3 Heguang Huang 4 Yu Pan 4 2 5
Affiliations

Affiliations

  • 1 Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
  • 2 Central Laboratory, Fujian Medical University Union Hospital, Fuzhou, Fujian, China.
  • 3 Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, China.
  • 4 Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, Fujian, China yupan199002@163.com heguanghuang22@163.com.
  • 5 The Cancer Center, Fujian Medical University Union Hospital, Fuzhou, China.
  • # Contributed equally.
Abstract

Objective: Pancreatic Cancer is an incurable malignant disease with extremely poor prognosis and a complex tumor microenvironment. We sought to characterize the role of Annexin A1 (ANXA1) in pancreatic Cancer, including its ability to promote efferocytosis and antitumor immune responses.

Methods: The tumor expression of ANXA1 and cleaved Caspase-3 (c-Casp3) and numbers of tumor-infiltrating CD68+ macrophages in 151 cases of pancreatic Cancer were examined by immunohistochemistry and immunofluorescence. The role of ANXA1 in pancreatic Cancer was investigated using myeloid-specific ANXA1-knockout mice. The changes in tumor-infiltrating immune cell populations induced by ANXA1 deficiency in macrophages were assessed by single-cell RNA Sequencing and flow cytometry.

Results: ANXA1 expression in pancreatic Cancer patient samples correlated with the number of CD68+ macrophages. The percentage of ANXA1+ tumor-infiltrating macrophages negatively correlated with c-Casp3 expression and was significantly associated with worse survival. In mice, myeloid-specific ANXA1 deficiency inhibited tumor growth and was accompanied by the accumulation of apoptotic cells in pancreatic tumor tissue caused by inhibition of macrophage efferocytosis, which was dependent on cGAS-STING pathway-induced type I interferon signaling. ANXA1 deficiency significantly remodeled the intratumoral lymphocyte and macrophage compartments in tumor-bearing mice by increasing the number of effector T cells and pro-inflammatory macrophages. Furthermore, combination therapy of ANXA1 knockdown with gemcitabine and anti-programmed cell death protein-1 antibody resulted in synergistic inhibition of pancreatic tumor growth.

Conclusion: This research uncovers a novel role of macrophage ANXA1 in pancreatic Cancer. ANXA1-mediated regulation of efferocytosis by tumor-associated macrophages promotes antitumor immune response via STING signaling, suggesting potential treatment strategies for pancreatic Cancer.

Keywords

Immunotherapy; Macrophage; Tumor microenvironment - TME.

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