Ontogeny of Tumor-Associated Macrophages and Its Implication in Cancer Regulation

Macrophages originate from both embryonic precursors and adult monocytes. Both proliferation and differentiation contribute to macrophage homeostasis. Monocyte-derived tiTAMs are prominent among many tumors. tiTAM differentiation can be controlled by discrete differentiation pathways. TAM origin helps determine its function in the control of tumor development. Macrophages are innate immune cells with evolutionarily conserved functions in tissue maintenance and host defense. As such, macrophages are among the first hematopoietic cells that seed developing tissues, and respond to inflammatory insults by in situ proliferation or de novo differentiation from monocytes. Recent studies have revealed that monocyte-derived tumor-induced macrophages represent a major tumor-associated macrophage (TAM) population, which can further expand following their differentiation in tumors. Compared with tissue-resident (tr)TAMs, these newly differentiated cells are phenotypically distinct, and likely have a unique role in tissue dysregulation and immune modulation in cancer. These findings imply that tumor growth elicits a specific innate immune response. In this review, we explore the different routes of macrophage seeding and maintenance in tissues during steady state and inflammation, and how these principles underlie the responses observed during tumor development. In addition, we highlight the relationship between the origin and function of macrophages in different settings and how this knowledge may be used to create new opportunities for cancer immunotherapy. Macrophages are innate immune cells with evolutionarily conserved functions in tissue maintenance and host defense. As such, macrophages are among the first hematopoietic cells that seed developing tissues, and respond to inflammatory insults by in situ proliferation or de novo differentiation from monocytes. Recent studies have revealed that monocyte-derived tumor-induced macrophages represent a major tumor-associated macrophage (TAM) population, which can further expand following their differentiation in tumors. Compared with tissue-resident (tr)TAMs, these newly differentiated cells are phenotypically distinct, and likely have a unique role in tissue dysregulation and immune modulation in cancer. These findings imply that tumor growth elicits a specific innate immune response. In this review, we explore the different routes of macrophage seeding and maintenance in tissues during steady state and inflammation, and how these principles underlie the responses observed during tumor development. In addition, we highlight the relationship between the origin and function of macrophages in different settings and how this knowledge may be used to create new opportunities for cancer immunotherapy.