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

Abstract

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 population, which can further expand following their differentiation in tumors. Compared to tissue-resident tumor-associated macrophages, these newly differentiated cells are phenotypically distinct, and likely play 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.

Figure 1. Tissue-resident macrophage origins

Macrophages arise from multiple sources during embryonic development. In mice, at embryonic day (E) 7–7.5 primitive hematopoiesis begins in the yolk sac with the emergence of “early” erythro-myeloid progenitors (EMPs) from the yolk sac blood islands. These precursors give rise to yolk sac macrophages, which colonize embryonic tissues including the head after establishment of blood circulation (E8.5). In the brain, yolk sac macrophages differentiate into microglia without a monocytic intermediate. The second hematopoietic wave, transient definitive hematopoiesis, is marked by “late” EMPs arising from the yolk sac hemogenic endothelium (approximately E8.5) and traveling to the fetal liver where they expand and give rise to fetal monocytes. These fetal monocytes begin to enter the circulation at E11.5–12.5 and seed the majority of tissue-resident macrophage populations. The final “definitive” wave of hematopoiesis begins when hematopoietic stem cells (HSCs) and their precursors in the para-aortic splanchnopleura (P-sp) and the aorta, gonads, and mesonephros (AGM) regions emerge and seed the fetal liver (E10.5). At E13.5–14.5, subsequent to the first wave of “late” EMP-derived fetal monocytes entering the circulation, pre-HSCs and HSCs give rise to fetal monocytes (and potentially tissue-resident macrophages, dashed arrow), before migration to the spleen and bone marrow. Here, HSCs give rise to all other lineages of the hematopoietic system, including “adult” monocytes that differentiate into a limited number of tissue-resident macrophage populations.

Figure 2. Tumor-associated macrophage origins

During steady state, tissue-resident macrophages are derived either from embryonic progenitors that seed tissues during development and maintain their population independently from blood-borne precursors in the adult, or from hematopoietic stem cells (HSC)-derived circulating monocytes. In developing tumors, tumor-associated macrophages (TAMs) can originate from tissue-resident macrophages of either embryonic or monocytic origin that may undergo a change in phenotype/activation state during carcinogenesis (Tissue-resident TAMs), or from monocytes that undergo a distinct differentiation step to become macrophages in response to tumor growth (Tumor-induced TAMs). Monocytes can also enter tumor tissue and undergo phenotypic changes without differentiation into macrophages (tumor-induced effector monocyte). Gray arrows signify migration, solid arrows (black and red) denote differentiation, and dashed arrows represent possible polarization/change in activation state.

Figure 3. Macrophage function during steady state and inflammation

Macrophages serve diverse functions to maintain tissue homeostasis. During steady state, both monocyte-derived and embryonic progenitor-derived macrophages perform generalized homeostatic roles as well as functions specialized to specific demands of the tissue. During infection, macrophages participate in pathogen recognition and host defense responses. In most infectious settings, monocyte-derived macrophages are recruited to tissues to engage Type I responses. In contrast, a subset of pathogens elicits a Type II immune response, which is largely orchestrated by expansion of tissue-resident macrophages. Tumor-associated macrophages (TAMs) contribute to tumor growth through dysregulated homeostatic functions and modulation of the adaptive immune system. Monocyte-derived tumor-induced TAMs (tiTAMs) are largely responsible for these protumor functions. The role of tissue-resident TAMs (trTAMs) in tumors remains to be determined.