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. Author manuscript; available in PMC: 2022 Jan 7.
Published in final edited form as: Nat Rev Cancer. 2021 Jun 8;21(8):526–536. doi: 10.1038/s41568-021-00366-w

FIG. 1 |. A unique set of mediators informs the communication between cancer stem cells and innate immune cell populations.

FIG. 1 |

Reciprocal communication between cancer stem cells (CSCs) and myeloid cells through soluble mediators or juxtacrine signalling promotes immunosuppression and stemness. a | CSCs drive monocytes and macrophages via molecules including C-C motif chemokine 2 (CCL2), CCL5, colony-stimulating factor 1 (CSF1), transforming growth factor-β (TGFβ), growth/differentiation factor 15 (GDF15), WNT-induced signalling protein 1 (WISP1) and periostin that bind to surface receptors, including CSF1 receptor (CSF1R) and C-C chemokine receptor type 2 (CCR2). Macrophages, in return, express factors including interleukin-6 (IL-6), IL-13, pleiotrophin and TGFβ that signal through receptors such as receptor-type tyrosine-protein phosphatase-ζ (PTPRZ1) and ephrin type A receptor 4 (EPHA4) to support CSCs. These interactions activate the downstream signal transducer and activator of transcription 3 (STAT3), AKT and nuclear factor-κB (NF-κB) pathways. CSCs also evade macrophage phagocytosis through CD47 expression. b | CSCs interfere with dendritic cell (DC) maturation through major histocompatibility complex class I antigen G (MHC-G)–immunoglobulin-like transcript (ILT) inhibitory receptor interaction. Tolerogenic DCs release C-X-C motif chemokine 12 (CXCL12), which serves as a ligand to C-X-C chemokine receptor type 4 (CXCR4) and CXCL1 to promote CSCs. These interactions lead to the activation of the stem cell transcription factors NANOG, OCT4, SOX2 and MYC. c | Nitric oxide (NO) produced by monocytic myeloid-derived suppressor cells (M-MDSCs) activates Notch on CSCs, and IL-6 signalling increases STAT3 phosphorylation. CSCs recruit M-MDSCs via macrophage migration inhibitory factor (MIF) through CD74. CSCs also promote arginase 1 and STAT3 signalling in M-MDSCs. d | The CXCL5–CXCR2 axis and granulocyte colony-stimulating factor (G-CSF) recruit tumour-associated neutrophils (TANs) and polymorphonuclear MDSCs (PMN-MDSCs). In return, prostaglandin E2 (PGE2) and S100A9 support stemness. TGFβ has a bidirectional role in this communication axis. Dashed arrows indicate indirect associations. G-CSFR, granulocyte colony-stimulating factor receptor; IL-6R, interleukin-6 receptor.