Notch Signaling Regulates Immunosuppressive Tumor-Associated Macrophage Function in Pancreatic Cancer
Recommended Citation
Yan W, Menjivar RE, Bonilla ME, Steele NG, Kemp SB, Du W, Donahue KL, Brown K, Carpenter ES, Avritt FR, Irizarry-Negron VM, Yang S, Burns WR, Zhang Y, Pasca di Magliano M, and Bednar F. Notch signaling regulates immunosuppressive tumor-associated macrophage function in pancreatic cancer. Cancer Immunol Res 2023; 12(1):91-106.
Document Type
Article
Publication Date
1-3-2024
Publication Title
Cancer Immunol Res
Abstract
Pancreatic ductal adenocarcinoma (PDA) continues to have a dismal prognosis. The poor survival of patients with PDA has been attributed to a high rate of early metastasis and low efficacy of current therapies, which partly result from its complex immunosuppressive tumor microenvironment. Previous studies from our group and others have shown that tumor-associated macrophages (TAM) are instrumental in maintaining immunosuppression in PDA. Here, we explored the role of Notch signaling, a key regulator of immune response, within the PDA microenvironment. We identified Notch pathway components in multiple immune cell types within human and mouse pancreatic cancer. TAMs, the most abundant immune cell population in the tumor microenvironment, expressed high levels of Notch receptors, with cognate ligands such as JAG1 expressed on tumor epithelial cells, endothelial cells, and fibroblasts. TAMs with activated Notch signaling expressed higher levels of immunosuppressive mediators, suggesting that Notch signaling plays a role in macrophage polarization within the PDA microenvironment. Genetic inhibition of Notch in myeloid cells led to reduced tumor size and decreased macrophage infiltration in an orthotopic PDA model. Combination of pharmacologic Notch inhibition with PD-1 blockade resulted in increased cytotoxic T-cell infiltration, tumor cell apoptosis, and smaller tumor size. Our work implicates macrophage Notch signaling in the establishment of immunosuppression and indicates that targeting the Notch pathway may improve the efficacy of immune-based therapies in patients with PDA.
Medical Subject Headings
Humans; Mice; Animals; Tumor-Associated Macrophages; Endothelial Cells; Pancreatic Neoplasms; Signal Transduction; Carcinoma, Pancreatic Ductal; Tumor Microenvironment
PubMed ID
37931247
ePublication
ePub ahead of print
Volume
12
Issue
1
First Page
91
Last Page
106
