Abstract
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 C1qa, C1qb, Trem2, and Chil3 Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated C1qa, C1qb, and Trem2, the other with high Chil3, Ly6c2 and Plac8 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 C1QA, C1QB, and TREM2 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.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a dismal 5-yr survival rate of only 10% (Siegel et al, 2020)
We found that livers and PBMCs from tumor-bearing mice had an increase in myeloid cells preceding the outgrowth of metastases, similar to previous reports (Rhim et al, 2012; Sanford et al, 2013; Li et al, 2018; Lee et al, 2019) (Fig S1A and B)
Having identified Chil3, triggering receptor expressed on myeloid cells 2 (Trem2), and the complement genes, C1qa and C1qb as markers of SAMs in tumor-bearing mice, we investigated whether these macrophage subsets exist in primary tumors
Summary
Pancreatic ductal adenocarcinoma (PDA) is a lethal malignancy with a dismal 5-yr survival rate of only 10% (Siegel et al, 2020). PDA is characterized by an abundant, fibroinflammatory stroma. From the onset of carcinogenesis, the immune response to pancreatic cancer results in an immunosuppressive tumor microenvironment (TME) (Clark et al, 2007). Myeloid cells are abundant and heterogeneous within the PDA TME and are a key driver of an immune suppressive microenvironment (Mitchem et al, 2013; Stromnes et al, 2014; Zhang et al, 2017; Zhu et al, 2014, 2017). The primary tumor and metastatic sites are both characterized by tumor cell evasion of the immune response (Hanahan & Weinberg, 2011; Gonzalez et al, 2018). The stochastic nature of metastasis greatly limits our ability to study the systemic responses to the primary tumor, recent advances in biomaterials engineering provide a novel opportunity to evaluate systemic response to PDA through the use of polycaprolactone scaffolds
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