Coordinated regulation of myeloid cells by tumours

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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.

Key Points

  • Tumours directly affect mature myeloid cells by converting some of them into immunosuppressive populations that facilitate tumour growth.

  • In cancer, normal myeloid cell differentiation is also diverted from its intrinsic pathway of terminal differentiation to mature myeloid cells (dendritic cells, macrophages and granulocytes) towards a pathway that generates pathologically activated immature cells, which are known as myeloid-derived suppressor cells (MDSCs).

  • MDSCs are immunosuppressive, immature and pathologically activated myeloid cells. However, in the absence of tumour-derived factors, they are still able to differentiate into mature myeloid cells. MDSCs consist of two major populations: polymorphonuclear MDSCs and monocytic MDSCs. MDSCs suppress antigen-specific and nonspecific immune responses through a variety of mechanisms.

  • Myeloid cell responses in cancer are regulated by common tumour-derived factors that activate a diverse set of transcription factors shared by myeloid cells. These transcription factors promote myelopoiesis and initiate the immunosuppressive pathways that commit immature myeloid cells to become MDSCs.

  • A two-stage model of MDSC involvement in tumour development and progression is proposed. A universal feature of tumour progression is the activation of abnormal myelopoiesis and the recruitment of immature myeloid cells into tissues. These cells may or may not possess immunosuppressive features, depending on the activation signals provided by the tumour microenvironment. If immunosuppression is not a property of the first wave of immature myeloid cells that are recruited to tumours, continuous stimulation of myelopoiesis and activation of immature myeloid cells by tumour-derived factors drives the subsequent accumulation of immunosuppressive MDSCs, which support tumour growth and the formation of the metastatic niche.

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Figure 1: Myeloid cell differentiation under normal physiological conditions.
Figure 2: The tumour microenvironment polarizes macrophages towards a tumour-promoting phenotype.
Figure 3: Changes that occur in myeloid cells in cancer.
Figure 4: Mechanisms of MDSC-dependent inhibition of T cell activation and proliferation.
Figure 5: Molecular mechanisms affecting the myeloid lineage in cancer.

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Correspondence to Dmitry I. Gabrilovich or Suzanne Ostrand-Rosenberg or Vincenzo Bronte.

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Glossary

Myeloid-derived suppressor cells

(MDSCs). A group of immature CD11b+GR1+ cells that includes precursors of macrophages, granulocytes, dendritic cells and myeloid cells. These cells are produced in response to various tumour-derived cytokines and have been shown to inhibit tumour-specific immune responses.

Pathogen-associated molecular patterns

(PAMPs). These are molecular motifs that are found in pathogens but not in mammalian cells. Examples include terminally mannosylated and polymannosylated compounds, which bind to the mannose receptor CD206, and various microbial products that activate host Toll-like receptors, such as bacterial lipopolysaccharides, hypomethylated DNA, flagellin and double-stranded RNA.

Damage-associated molecular patterns

(DAMPs). As a result of cellular stress, cellular damage and non-physiological cell death, DAMPs are released from the degraded stroma (in the case of hyaluronate, for example), from the nucleus (in the case of high-mobility group box 1 protein (HMGB1), for example) and from the cytoplasm (for example, in the case of ATP, uric acid, S100 calcium-binding proteins and heat-shock proteins). Such host-derived DAMPs are thought to promote local inflammatory reactions.

TH2 cells

(T helper 2 cells). CD4+ T cells are classified on the basis of the types of effector cytokine that they secrete. TH2 cells produce interleukin-4 (IL-4), IL-5 and IL-13, and they support humoral immunity and downregulate TH1 cell responses.

TH1 cells

(T helper 1 cells). TH1 cells produce interferon-γ, lymphotoxin-α and tumour necrosis factor, and they support cell-mediated immunity. An imbalance between TH1 cell responses and TH2 cell responses is thought to contribute to the pathogenesis of various infections, allergic responses and autoimmune diseases.

Mixed leukocyte reaction

A tissue-culture technique for testing T cell reactivity and antigen-presenting cell (APC) activity. A population of T cells is cultured with MHC-mismatched APCs, and the proliferation of the T cells is determined by measuring the incorporation of 3H-thymidine into the DNA of dividing cells.

Indoleamine 2,3-dioxygenase

(IDO). An intracellular haem-containing enzyme that catalyses the oxidative catabolism of tryptophan. IDO suppresses T cell responses and promotes immune tolerance in mammalian pregnancy, tumour resistance, chronic infection, autoimmunity and allergic inflammation.

Regulatory T cells

(TReg cells). A specialized subset of CD4+ T cells that can suppress both innate and adaptive immune responses. These cells provide a crucial mechanism for the maintenance of peripheral self-tolerance, but may also limit the effectiveness of antitumour immune responses.

Plasminogen

Plasminogen is the inactive precursor of plasmin, a serine protease involved in the dissolution of fibrin blood clots. A causal role has been suggested for plasmin generation in cancer cell invasion through extracellular matrix remodelling.

Invariant NKT cells

(Invariant natural killer T cells). A type of lymphocyte thought to be particularly important in bridging innate and adaptive immunity. These cells express a particular T cell receptor variable gene segment (Vα14 in mice and Vα24 in humans) that is precisely linked to a particular joining (Jα) gene segment. Typically, NKT cells co-express cell-surface markers encoded by the natural killer locus, and are activated by recognition of CD1d.

Natural TReg cells

A subset of TReg cells that undergoes maturation in the thymus, where these cells acquire the ability to recognize with intermediate avidity self antigens presented by host MHC class II molecules before being released to the periphery.

Induced TReg cells

A subset of TReg cells that is derived from the direct conversion of CD4+ naive T cells in peripheral lymphoid organs in several situations, including the interaction with tumour-conditioned myelomonocytic cells in tumour-bearing hosts.

TH17 cell

(T helper 17 cell). A CD4+ T helper cell that produces IL-17 and that is thought to be important in mediating host defence against certain infections, particularly at mucosal tissues. These cells are also thought to drive pathology in certain inflammatory and autoimmune diseases, such as Crohn's disease.

Autochthonous tumour

Differently from transplanted tumours, which arise from the experimental transfer of neoplastic cells or tissues, autochthonous tumours develop spontaneously in the host. Autochthonous tumours can be derived from either chemical carcinogenesis or targeted tissue expression of oncogenes by genetic manipulation of mice.

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Gabrilovich, D., Ostrand-Rosenberg, S. & Bronte, V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol 12, 253–268 (2012) doi:10.1038/nri3175

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