Myeloid cells are a subpopulation of hematopoietic cells and originate from a network of hematopoietic stem cells (HSC) and multi-potent progenitor cells (MPP). The network of progenitor cells that gives rise to various hematopoietic cells includes common myeloid progenitor cells (CMP); common lymphoid progenitor cells (CLP); MΦ and DC progenitors (MDP); common DC progenitors (CDP), granulocyte/macrophage progenitors (GMP), megakaryocyte/erythroid progenitors (MEP); - mast cell progenitors (MCP). cDC – conventional DCs, pDC – plasmacytoid DCs

Tumor cells produce factors that drive the generation of multiple regulatory cells, including CD4⁺ Th2, T_regs, B cells, and MDSC. Tumor cells also modify their microenvironment to produce hypoxia and inflammation (thin black arrows). The regulatory cells and the modified tumor microenvironment subsequently produce cytokines, chemokines, and other molecules that polarize MΦ by regulating MΦ gene expression (e.g. Tie2, HLA-DR, CD163, etc.), by modifying MΦ cytokine expression (e.g. IL-10, IL-12, etc.) and by enhancing MΦ recruitment to the tumor site (thick gray arrows). Tumors also produce factors (ie. TNFα, etc.) that directly polarize MΦ. The resulting MΦ share some characteristics with alternatively activated MΦ and other characteristics unique to TAMs. Cross-talk between tumor cells and MDSC and between tumor cells and inflammation within the tumor microenvironment amplify the effects (thin black double-headed arrows). See the text for references and for which molecules and cellular interactions are known for murine macrophages vs. human macrophages.

Factors in the tumor microenvironment produced by tumor cells and stromal cells (including myeloid cells) modulate myeloid cell phenotype and function. iMC – denote immature myeloid cells, a combination of myeloid progenitors described in . Thin dotted line - regular pathways of myeloid cell differentiation from iMC to DCs, MΦ and granulocytes. Solid thick lines – pathways of myeloid cell differentiation in cancer. Dotted thick line – suggested, not yet confirmed direction of myeloid cell differentiation. supDCs – DC with immune suppressive activity. TAM- tumor associated MΦ.

Myeloid cells conditioned by tumors can induce paralysis of T lymphocytes by expanding/converting T_regs (top left), depriving the environment of amino acids (top right), releasing oxidizing molecules (bottom left), and/or altering T cell migratory properties and viability (bottom right). Since induction of these pathways is regulated by common transcription factors, they can operate in more than one myeloid cell type, as reported in . By binding to RAGE, S100A8/A9 also provides autocrine stimulation (middle left). TGFβ, transforming growth factor-β; X_c-, cystine/glutamate transporter; CAT2B, cationic amino acid transporter (L-arginine transporter); ASC, sodium-dependent neutral amino acid transporter (L-cysteine transporter); IFNγ, interferon-γ; IL, interleukin; MYD88, myeloid differentiation primary response protein 88; HIF-1α, hypoxia inducible factor 1α; CEBPβ, CCAAT/enhancer-binding protein β; FOXP3, forkhead box protein P3; Phox, phagocyte oxidase; STAT, signal transducer and activator of transcription; NO, nitric oxide; ARG, arginase; NOS, nitric oxide synthase; Gal9, galectin 9; TIM3, T-cell immunoglobulin and mucin domain-containing protein 3; ADAM17, a disintegrin and metalloproteinase domain 17; CD62L, L-selectin. S100A8/A9, S100 calcium binding protein A8/A9; RAGE, receptor for advanced glycation end products.

The tumour microenvironment secretes many different cytokines (green circles) that affect myeloid progenitors as well as mature myeloid cells by regulating the activity of multiple transcription factors (blue). These transcription factors, in turn, regulate synthesis of their protein targets (yellow) affecting myeloid cell functions (black).