Pancreatic cancer is marked by complement-high blood monocytes and tumor-associated macrophages

• Published in: Life science alliance 2021-06, Vol.4 (6), p.e202000935
• Main Authors: Kemp, Samantha B, Steele, Nina G, Carpenter, Eileen S, Donahue, Katelyn L, Bushnell, Grace G, Morris, Aaron H, The, Stephanie, Orbach, Sophia M, Sirihorachai, Veerin R, Nwosu, Zeribe C, Espinoza, Carlos, Lima, Fatima, Brown, Kristee, Girgis, Alexander A, Gunchick, Valerie, Zhang, Yaqing, Lyssiotis, Costas A, Frankel, Timothy L, Bednar, Filip, Rao, Arvind, Sahai, Vaibhav, Shea, Lonnie D, Crawford, Howard C, Pasca di Magliano, Marina
• Format: Article
• Language: English
• Subjects: Adult; Animals; Carcinoma, Pancreatic Ductal - genetics; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Carrier Proteins; Complement C1q; Female; Gene Expression - genetics; Gene Expression Regulation, Neoplastic - genetics; Humans; Macrophages - metabolism; Male; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Monocytes - metabolism; Pancreatic Neoplasms; Pancreatic Neoplasms - blood; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Receptors, Complement; Receptors, Immunologic - metabolism; Sequence Analysis, RNA; Single-Cell Analysis; Transcriptome - genetics; Tumor Microenvironment - genetics; Tumor-Associated Macrophages - metabolism; Tumor-Associated Macrophages - physiology
• ISSN: 2575-1077; 2575-1077
• DOI: 10.26508/lsa.202000935

Pancreatic ductal adenocarcinoma (PDA) is accompanied by reprogramming of the local microenvironment, but changes at distal sites are poorly understood. We implanted biomaterial scaffolds, which act as an artificial premetastatic niche, into immunocompetent tumor-bearing and control mice, and identified a unique tumor-specific gene expression signature that includes high expression of , , , and Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated , , and , the other with high , and In mice, expression of these genes in the corresponding populations was elevated in tumor-associated macrophages compared with macrophages in the normal pancreas. We then analyzed single-cell RNA sequencing from patient samples, and determined expression of , , and is elevated in human macrophages in primary tumors and liver metastases. Single-cell sequencing analysis of patient blood revealed a substantial enrichment of the same gene signature in monocytes. Taken together, our study identifies two distinct tumor-associated macrophage and monocyte populations that reflects systemic immune changes in pancreatic ductal adenocarcinoma patients.