Single-cell RNA profiling reveals classification and characteristics of mononuclear phagocytes in colorectal cancer.

Colorectal cancer (CRC) is a major cause of cancer mortality and a serious health problem worldwide. Mononuclear phagocytes are the main immune cells in the tumor microenvironment of CRC with remarkable plasticity, and current studies show that macrophages are closely related to tumor progression, invasion and dissemination. To understand the immunological function of mononuclear phagocytes comprehensively and deeply, we use single-cell RNA sequencing and classify mononuclear phagocytes in CRC into 6 different subsets, and characterize the heterogeneity of each subset. We find that tissue inhibitor of metalloproteinases (TIMPs) involved in the differentiation of proinflammatory and anti-inflammatory mononuclear phagocytes. Trajectory of circulating monocytes differentiation into tumor-associated macrophages (TAMs) and the dynamic changes at levels of transcription factor (TF) regulons during differentiation were revealed. We also find that C5 subset, characterized by activation of lipid metabolism, is in the terminal state of differentiation, and that the abundance of C5 subset is negatively correlated with CRC patients' prognosis. Our findings advance the understanding of circulating monocytes' differentiation into macrophages, identify a new subset associated with CRC prognosis, and reveal a set of TF regulons regulating mononuclear phagocytes differentiation, which are expected to be potential therapeutic targets for reversing immunosuppressive tumor microenvironment. Author summary: Colorectal cancer (CRC) is a serious health problem worldwide. Mononuclear phagocytes are the main immune cells in the tumor microenvironment of CRC with remarkable plasticity. In this study, single-cell RNA sequencing technology was used to study the subsets and characteristics of mononuclear phagocytes in CRC. We classify mononuclear phagocytes in CRC into 6 different subsets and demonstrate the heterogeneity in infiltrating mononuclear phagocytes of CRC. We find that tissue inhibitor of metalloproteinases (TIMPs) involved in the differentiation of proinflammatory and anti-inflammatory mononuclear phagocytes and reveal the trajectory and characteristics of circulating monocytes differentiation into tumor-associated macrophages (TAMs). We also find a new immunosuppressive subset of mononuclear phagocytes, which is associated with the prognosis of CRC patients. Our findings identify the heterogeneity in infiltrating mononuclear phagocytes of CRC, find a new subset associated with CRC prognosis. Also, we reveal the differentiation of mononuclear phagocytes would lead to an immunosuppressive tumor microenvironment and provide potential targets for reversing the process. [ABSTRACT FROM AUTHOR]