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Review
. 2021 Aug;21(8):526-536.
doi: 10.1038/s41568-021-00366-w. Epub 2021 Jun 8.

Cancer stem cell-immune cell crosstalk in tumour progression

Defne Bayik  1   2 , Justin D Lathia  3   4
Affiliations
Review

Cancer stem cell-immune cell crosstalk in tumour progression

Defne Bayik et al. Nat Rev Cancer. 2021 Aug.

Abstract

Cellular heterogeneity and an immunosuppressive tumour microenvironment are independent yet synergistic drivers of tumour progression and underlie therapeutic resistance. Recent studies have highlighted the complex interaction between these cell-intrinsic and cell-extrinsic mechanisms. The reciprocal communication between cancer stem cells (CSCs) and infiltrating immune cell populations in the tumour microenvironment is a paradigm for these interactions. In this Perspective, we discuss the signalling programmes that simultaneously induce CSCs and reprogramme the immune response to facilitate tumour immune evasion, metastasis and recurrence. We further highlight biological factors that can impact the nature of CSC-immune cell communication. Finally, we discuss targeting opportunities for simultaneous regulation of the CSC niche and immunosurveillance.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

FIG. 1 |
FIG. 1 |. A unique set of mediators informs the communication between cancer stem cells and innate immune cell populations.
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.
FIG. 2 |
FIG. 2 |. CSCs interfere with T cell activity directly or through immunosuppressive myeloid cells.
Cancer stem cells (CSCs) suppress or evade antitumorigenic T cells in part by releasing extracellular vesicle (EV)-associated or free tenascin C (TNC) and reducing AKT and ERK signalling. CSCs also induce tumour-promoting regulatory T cells (Treg cells) and T helper 17 (TH17) cells. CSCs downregulate major histocompatibility complex class I (MHC-I) and overexpress checkpoint regulators, including programmed cell death 1 ligand 1 (PDL1). CSCs further drive recruitment and polarization of TH17 cells and Treg cells by the combination of C-C motif chemokine 1 (CCL1), CCL2, CCL5, transforming growth factor-β (TGFβ) and indoleamine 2,3-dioxygenase 1 (IDO1). An additional layer of regulation of T cell activity is mediated indirectly by immunosuppressive myeloid cells, including macrophages and monocytic myeloid-derived suppressor cells (M-MDSCs). This effect partially depends on CCL1, CCL2, CCL5, interleukin-4 (IL-4), IL-6 and IL-10 secreted by CSCs. Myeloid cells produce additional suppressive molecules, such as the checkpoint inhibitor ligand PDL1, to block T cell activation in a contact-dependent manner or by promoting Treg cells. Collectively, these interactions reshape the tumour microenvironment and create a habitat where Treg cells and TH17 cells support CSCs, the latter via IL-17 production. STAT3, signal transducer and activator of transcription 3.
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