Coordinated regulation of myeloid cells by tumours

Abstract

Myeloid cells are the most abundant nucleated haematopoietic cells in the human body and are a collection of distinct cell populations with many diverse functions. The three groups of terminally differentiated myeloid cells - macrophages, dendritic cells and granulocytes - are essential for the normal function of both the innate and adaptive immune systems. Mounting evidence indicates that the tumour microenvironment alters myeloid cells and can convert them into potent immunosuppressive cells. Here, we consider myeloid cells as an intricately connected, complex, single system and we focus on how tumours manipulate the myeloid system to evade the host immune response.

Figure 1. Myeloid cell differentiation under normal physiological conditions

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

Figure 2. The tumor microenvironment polarizes macrophages towards a tumor-promoting phenotype

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.

Figure 3. Changes that occur in myeloid cells in cancer

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 Figure 1. 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.

Figure 4. Mechanisms of myeloid cell-dependent inhibition of T cell activation and proliferation

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 Figure 5. 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.

Figure 5. Molecular mechanisms affecting myeloid lineage in cancer

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).