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* * Immature myeloid cells (IMCs) are part of the normal process of myelopoiesis, which takes place in the bone marrow and is controlled by a complex network of soluble factors that include cytokines such as granulocyte/macrophage colony-stimulating factor (GM-CSF), stem-cell factor (SCF), interleukin-3 (IL-3), FMS-related tyrosine kinase 3 (FLT-3), macrophage colonystimulating factor (M-CSF) and cell-expressed molecules including Notch (not shown). Haematopoietic stem cells (HSCs) differentiate into common myeloid progenitor (CMP) cells and then into IMCs. Normally, IMCs migrate to different peripheral organs, where they differentiate into dendritic cells, macrophages and/or granulocytes. However, factors produced in the tumour microenvironment and/or during acute or chronic infections, trauma or sepsis, promote the accumulation of IMCs at these sites, prevent their differentiation and induce their activation. These cells exhibit immunosuppressive functions and are therefore known as myeloid-derived suppressor cells (MDSCs). MDSCs can also differentiate into tumorassociated macrophages (TAMs) within the tumour environment, which are cells that have a phenotype and function that is distinct from MDSCs. Gabrilovich and Nagaraj Page 20 Nat * * Figure 15-10 Signaling Pathways of AICDElements of the extrinsic and intrinsic apoptotic pathways are shown in blue and grey, respectively. Extrinsic pathway: prolonged TCR engagement delivers signals via ZAP-70 and NFAT that increase TNFR1 and Fas expression. Upon the binding of several FasL molecules expressed on an APC to Fas expressed on the activated T cell (only one pair is shown for clarity), the adaptor protein FADD is recruited to the cytoplasmic tail of the Fas molecule. FADD in turn recruits procaspase-8, which cleaves itself to generate active caspase-8. Caspase-8 cleaves procaspase-3 to activate this key executioner enzyme, which in turn cleaves procaspase-6 and procaspase-7. Activated caspase-6 and -7 are responsi