Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment

Abstract

Ongoing research has revealed that the existence of cancer stem cells (CSCs) is one of the biggest obstacles in the current cancer therapy. CSCs make an influential function in tumor progression, recurrence and chemoresistance due to their typical stemness characteristics. CSCs are preferentially distributed in niches, and those niche sites exhibit characteristics typical of the tumor microenvironment (TME). The complex interactions between CSCs and TME illustrate these synergistic effects. The phenotypic heterogeneity within CSCs and the spatial interactions with the surrounding tumor microenvironment led to increased therapeutic challenges. CSCs interact with immune cells to protect themselves against immune clearance by exploiting the immunosuppressive function of multiple immune checkpoint molecules. CSCs also can protect themselves against immune surveillance by excreting extracellular vesicles (EVs), growth factors, metabolites and cytokines into the TME, thereby modulating the composition of the TME. Therefore, these interactions are also being considered for the therapeutic development of anti-tumor agents. We discuss here the immune molecular mechanisms of CSCs and comprehensively review the interplay between CSCs and the immune system. Thus, studies on this topic seem to provide novel ideas for reinvigorating therapeutic approaches to cancer.

Keywords: Cancer stem cells (CSCs); Immune cells; Tumor immune microenvironment (TIME).

Fig. 1

CSCs interfere with immune cell activity directly or through cytokines. CSCs suppress or evade antitumorigenic T cells in part by immune checkpoint (MHC-I, PD-L1 and CD80). CSCs reduce DCs mature and differentation via TGFβ and Ev (MHC-I, HLA-G). NKG2DL are able to kill MHC-I negative CSCs in an APC-independent manner. NK cells inhibitory ligands KIR2DL4 and NKG2A interact with HLA-G on CSCs and directly inhibits NK cells activation. CSCs further drive recruitment and polarization of TH17 cells and Treg cells by the combination of CCL-1, IL-2, IL-8, IL-10 and TGF-β1. Tregs produce TGF-β1 and IL-17 to promote self-renewal capacity, stem cell markers, and EMT toward tumor progression and invasion. CSCs also derived PD-L1 mediate the infiltration of Tregs. 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 CSF1, CCL2, CCL5, TGF-β1 and PEG-E2 secreted by CSCs. The pathway of CSCs expressing TIM-3/Galectin 9 (Gal-9) expands the number of MDSCs. Exosome S100A9 enhances STAT3/NF-κB phosphorylation and production of prostaglandin E2 (PEG-E2) to promote CSCs. 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

Fig. 2

Immune checkpoint targeting CSCs. Administrated NK cells or CAR NK cells target TAAs on CSCs. Ex vivo maturation of DCs exposed to CSCs-lysate/TAAs/peptides produce a vaccine that after administration arm the cytotoxic T cells in an MHC-1-TCR-dependent manner for targeting specifc CSCs. Antibodies targeting immune checkpoint molecules such as PD1/PDL1, CD276, and CTLA4 could improve the anticancer immune responses. Anti-CD47 antibody sensitizes CSCs to cell-mediated phagocytosis. FASL, FAS ligand; mDC, mature DC; TRAIL, TNF-related apoptosis-inducing ligand

Fig. 3

Crosstalk between CSCs and TME cells. CSCs secrete exosome regulated infltrating immune cells (IICs), MDSC, DC, macrophage and neutrophils to the TME. Cell–cell interactions in TME contribute to the development of cancer. The mechanism of interaction between CSCs and tumor-infiltrating immune cells is not only through immune targets, but can likewise be through exosomes that enable a large exchange