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

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.