Instruction of myeloid cells by the tumor microenvironment: Open questions on the dynamics and plasticity of different tumor-associated myeloid cell populations

Abstract

The versatility and plasticity of myeloid cell polarization/differentiation has turned out to be crucial in health and disease, and has become the subject of intense investigation during the last years. On one hand, myeloid cells provide a critical contribution to tissue homeostasis and repair. On the other hand, myeloid cells not only play an important role as first line defense against pathogens but also they are involved in a broad array of inflammation-related diseases such as cancer. Recent studies show that macrophages can exist in different activation states within the same tumor, underlining their plasticity and heterogeneity. In this review, we will discuss recent evidence on how the tumor microenvironment, as it evolves, shapes the recruitment, function, polarization and differentiation of the myeloid cell compartment, leading to the selection of myeloid cells with immunosuppressive and angiogenic functions that facilitate tumor progression and dissemination.

Figure 1. Ontogeny and differentiation of tumor-associated myeloid cells (adapted from Geissmann et al., Science 2010, 327:656 and Fridlender et al., Cancer Cell 2009, 16:183). In the bone marrow, hematopoietic stem cells give rise to common lymphoid (not shown) and common myeloid precursors (CMPs), which in turn give rise to monocyte/macrophage and dendritic cell precursors (MDPs) and granulocyte precursors (GPs). Via a pro-monocyte stage, Ly6C^hi and Ly6C^low monocytes are formed and leave the bone marrow to enter the blood. Highly monocyte-related cells include monocytic myeloid derived suppressor cells (MO-MDSCs) and Tie2-expressing monocytes (TEMs). Tissue-resident macrophages are primarily derived from yolk sac (YS) progenitors (Schulz et al., Science 2012, 236:86), although they may be derived from Ly6C^low monocytes when a replenishment of the population is needed. Under inflammatory conditions, Ly6C^hi monocytes can become monocyte-derived DCs (Mo-DCs) and inflammatory macrophages, which include M1-like and M2-like cells depending on the tumor microenvironment. In addition, Ly6C^hi monocytes may contribute to MO-MDSCs within tumors. Common dendritic cell precursors (CDPs) give rise to plasmacytoid dendritic cells (pDCs) and pre-DCs that become CD11b⁺-like and CD8⁺-like DCs in lymphoid tissues. The precise origin and type of TADCs requires further investigation. GPs give rise to neutrophils that in the tumor context can also polarize into an N1- and an N2-type phenotype. Granulocytic MDSCs (PMN-MDSCs) are immature precursors of mature neutrophils with a strong immunosuppressive capacity that, together with the immunosuppressive MO-MDSCs, accumulate in the periphery and in tumors. Dashed arrows represent possible differentiation pathways that require experimental confirmation.

Figure 2. Effects of the tumor on the induction, recruitment and differentiation of myeloid cells. Hypoxia, low pH and glucose deprivation induce an endoplasmic reticulum (ER) stress that leads to the unfolded protein response (UPR) and transcription of pro-inflammatory factors by neoplastic cells. An “infectious” UPR spreading to immune cells can alter their antigen-processing capacity and increase their production of inflammatory factors. Hypoxia also enhances angiogenesis via the induction of vascular endothelial growth factor (VEGF) and, together with tumor-derived exosomes, can increase the immunosuppressive activity of monocytic monocytic myeloid derived suppressor cells (MO-MDSCs), block their differentiation into dendritic cells (DCs) and enhance their conversion into MHC class II^low MMR^high M-2 type macrophages, which concentrate in hypoxic areas. Soluble and vesicle-associated factors produced by the neoplastic cell induce MDSC production/accumulation in bone marrow and periphery, and their recruitment to the tumor site. The possible interconversion between the different types of myeloid cells within the tumor, as well as their self-renewal capacity in situ (dashed arrows) are crucial questions that require further investigation and are thus depicted in gray. MMR, macrophage mannose receptor; PDGF, platelet growth factor; PIGF, placental growth factor; PGE₂, prostaglandin E₂.