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

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 <i>C1qa</i>, <i>C1qb</i>, <i>Trem2</i>, and <i>Chil3</i> Single-cell RNA sequencing mapped these genes to two distinct macrophage populations in the scaffolds, one marked by elevated <i>C1qa</i>, <i>C1qb</i>, and <i>Trem2</i>, the other with high <i>Chil3</i>, <i>Ly6c2</i> and <i>Plac8</i> 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 <i>C1QA</i>, <i>C1QB</i>, and <i>TREM2</i> 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.