Cancer Immunol Res. 2025 Jul 31. doi: 10.1158/2326-6066.CIR-24-0534. Online ahead of print.
ABSTRACT
Pancreatic adenocarcinoma (PDAC) has a dismal survival rate due to limited effective therapies. While studies have focused on innate immune cell influence on adaptive immune cell functions, few have explored interactions between innate immune cells, which modulate the unique PDAC tumor microenvironment (TME). Macrophages are responsible for clearance of neutrophil-mediated inflammation in physiologic immune responses; however, these cells co-exist in PDAC. We sought to determine how neutrophil extracellular traps (NETs), neutrophil release of decondensed chromatin and intracellular contents, affect monocyte/macrophage populations in the PDAC TME. Utilizing samples from patients with PDAC, we demonstrate elevated monocyte chemokine CCL2 in plasma and elevated NET CitH3 and pan-macrophage marker CD68 in the PDAC TME via fluorescent immunohistochemistry. To determine how NETs impacted macrophage populations in the PDAC TME, we depleted NETs with DNase I and with genetic knockout of the PAD4 enzyme and found an elevation in pan-macrophage marker F4/80. The depletion led to increased T cell stimulatory signal CD80 while the pro-tumor macrophage marker CD206 was decreased. We further demonstrate that macrophages in the NET-deficient PDAC TME may be recruited through the CCL2/CCR2 axis, in which CCL2 can be released from tumor cells and macrophages in the presence of IFN-. Taken together, our findings reveal that inhibition of NETs can prime the innate immune response toward an anti-tumor phenotype.
PMID:40742388 | DOI:10.1158/2326-6066.CIR-24-0534