Chapter 49 : Tumor-Induced Myeloid-Derived Suppressor Cells

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Tumors are composed of heterogeneous, transformed cell populations with different morphologies and phenotypes, which are organized in a pyramidal architecture determined by self-renewal ability, differentiation grade, and tumorigenic and clonogenic potential ( ). During tumor progression, cancer cells secrete tumor-derived factors (TDFs), like cytokines, chemokines, and metabolites, which promote the development of a flexible microenvironment inducing both the generation of new vessels and the modification of the immune responses ( ). Tumors can escape the immune system by three main mechanisms: (i) cancer cells can veil their identity to escape recognition by immune effectors, (ii) they can directly modify antitumor immunity, or (iii) they can recruit other immune regulatory cells whose normal function is to inhibit immune reactions and prevent the unfavorable effects of uncontrolled immune stimulation ( ). Probably the most pervasive and efficient strategy of “tumor escape” relies on the tumor’s ability to create a tolerant microenvironment by modification of normal hematopoiesis. In fact, cancers can induce the proliferation and differentiation of myeloid precursors into myeloid cells with immunosuppressive functions, in both the bone marrow and other hematopoietic organs such as the spleen, at the expense of additional myeloid cell subsets, such as dendritic cells (DCs) ( ). Additionally, the persisting imbalance in the number and type of myeloid cells can deeply influence myeloid cell recruitment and function at the tumor site and secondary lymphoid organs. In the bone marrow, hematopoietic progenitor cells give rise to immature DCs (iDCs). To reach complete maturation, iDCs require inflammation-related stimuli because, although able to take up, process, and present antigens, they express few or none of the costimulatory molecules, such as CD80, CD86, and CD40, necessary to exert their functions ( ). The higher number of iDCs found at the tumor site stems from defects in myelopoiesis rather than simply from the lack of appropriate activation signals at the tumor site. treatment of tumor-infiltrating DCs with appropriate stimuli—such as granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor α (TNF-α), or CD40L—was not sufficient to induce DC maturation; this evidence supports the concept that the reduced functionality of DCs is most likely due to defects in differentiation from their iDC progenitors ( ). However, iDCs are not the only myeloid cell populations modified in cancer. In postnatal life, hematopoietic stem cells present in hemopoietic compartments give rise to lymphoid and myeloid multipotent precursor cells. Other pluripotent cell types originate from the myeloid precursors: the common DCs and the immature myeloid cell precursors (IMCs). The first originates iDCs and plasmacytoid DCs, and the second is the common progenitor for macrophages, granulocytes, and monocyte-derived DCs ( ). In healthy mice, IMCs rapidly differentiate into their descendant lineages; consequently, they represent a relatively low percentage of circulating myeloid cells. However, under pathological conditions, including cancer, there is a partial block in IMC differentiation, leading to the accumulation of CD11b/Gr-1 myeloid cells with immunosuppressive function, named myeloid-derived suppressor cells (MDSCs) ( ).

Citation: De Sanctis F, Bronte V, Ugel S. 2017. Tumor-Induced Myeloid-Derived Suppressor Cells, p 833-856. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0016-2015
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MDSCs suppress the immune response by four main mechanisms. (1) MDSCs deplete essential metabolites for T lymphocyte fitness, such as -cysteine, -tryptophan (by the activation of IDO1), and -arginine (by the activation of both ARG1 and NOS2), inducing the T-cell proliferation arrest. T-cell proliferation block is exacerbated by MDSC-released TGF-β. -Arginine depletion by ARG1 activity also induces the translational repression of the CD3 ζ chain, which prevents T cells from responding to various stimuli. NO production inhibits T cells by interfering with the signaling cascade downstream of the IL-2 receptor. (2) High arginase activity in combination with increased NO production by the MDSCs not only results in more pronounced T-cell apoptosis but also leads to an increased production of ROS and RNS, such as the free radical peroxynitrite (ONOO), by the MDSCs. This process requires collaboration with NOX2 enzyme, which contributes to large amounts of ROS, such as HO, which then affect T-cell fitness by downregulating CD3 ζ-chain expression and reducing cytokine secretion. RNS can act on α and β TCR chains, preventing TCR signaling and promoting dissociation of CD3 ζ chain from the complex. (3) MDSCs interfere with T-cell migration and viability. MDSCs express the metalloproteinase ADAM17, able to cut the integrin CD62L on the T-cell membrane. RNS also modify leukocyte trafficking, promoting homing of immune-suppressive subsets other than T cells by tyrosine nitration of selective chemokines (like CCL2) or their receptors. MDSCs expressing PD-L1 can induce T-cell apoptosis by engaging PD-1. Moreover, NO produced by MDSCs has a direct proapoptotic role mediated by the accumulation of p53 and signaling by Fas, TNF receptor family members, and caspase-independent pathways. Finally, the MDSC-derived TGF-β can promote NK-cell inhibition. (4) MDSCs drive the differentiation of specific subsets into regulatory cells: by TGF-β release, MDSCs promote the clonal expansion of antigen-specific natural (n) Treg cells and drive the conversion of naive CD4 T cells into induced (i) Treg cells. MDSCs skew macrophages toward an M2 phenotype by release of IL-10. For abbreviations and more details, see the text.

Citation: De Sanctis F, Bronte V, Ugel S. 2017. Tumor-Induced Myeloid-Derived Suppressor Cells, p 833-856. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0016-2015
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