Monocyte heterogeneity and functions in cancer

Abstract

Monocytes are innate immune cells of the mononuclear phagocyte system that have emerged as important regulators of cancer development and progression. Our understanding of monocytes has advanced from viewing these cells as a homogenous population to a heterogeneous system of cells that display diverse responses to different stimuli. During cancer, different monocyte subsets perform functions that contribute to both pro- and antitumoral immunity, including phagocytosis, secretion of tumoricidal mediators, promotion of angiogenesis, remodeling of the extracellular matrix, recruitment of lymphocytes, and differentiation into tumor-associated macrophages and dendritic cells. The ability of cancer to evade immune recognition and clearance requires protumoral signals to outweigh ongoing attempts by the host immune system to prevent tumor growth. This review discusses current understanding of monocyte heterogeneity during homeostasis, highlights monocyte functions in cancer progression, and describes monocyte-targeted therapeutic strategies for cancer treatment.

Keywords: Monocytes; cancer; myeloid cells; tumor microenvironment.

Figure 1

Recruitment and functions of monocyte subsets to primary tumors and metastatic sites within the lung. Classical CCR2⁺ monocytes extravasate from the vasculature into primary tumor sites in response to CCL2. Classical monocytes are capable of producing tumoricidal mediators, but are likely reprogrammed within the tumor microenvironment to limit their cytotoxicity. Tumor‐educated monocytes differentiate into TAMs or moDCs. Monocyte‐derived TAMs facilitate tumorigenesis by promoting immune suppression (inhibition of CD8⁺ T cell recruitment/activities and recruitment of Treg), ECM remodeling, angiogenesis, and tumor cell intravasation into the vasculature. Tie‐2⁺ monocytes/Mϕs display pro‐angiogenic functions within primary tumors, although a role for nonclassical patrolling monocytes (PMo) in primary tumors remains unclear. In lung metastatic sites, classical monocytes are recruited in a CCL2‐dependent manner, promote metastatic seeding, and have similar protumoral effects. PMo home to tumor metastases in a CX3CL1/CX3CR1‐dependent manner, where they engulf tumor material and produce chemokines that stimulates recruitment of cytotoxic NK cells. Tumor‐derived microparticles within the vasculature expand bone marrow pools of PMo to increase immune surveillance. Tumor immune evasion within primary and metastatic sites requires protumoral signals to outweigh ongoing attempts by the host immune system to prevent tumor growth