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. 2019 Dec 13;10:2895. doi: 10.3389/fimmu.2019.02895

Figure 1.

Figure 1

Crosstalk of ILCs and the different components of the tumor microenvironment. NK cells are the main ILC subset found in the TME, after migrating from the blood in a CXCR3-dependent way. They play important roles in (1) immune recruitment, (2) tumor cell killing, (3) extracellular matrix (ECM) remodeling, and (4) angiogenesis. (1) NK cells recruit cDC1s to the TME by secreting CCL5 and XCL1/2, and promote their survival and maturation through FLT3L and IFNγ. (2) NK cell mediated killing is mostly achieved by the engagement of death receptors (e.g., Fas/FasL) and by the release of cytotoxic granules containing perforin (Prf1) and granzymes (GrzB). This response can be triggered by the expression of stress markers on tumor cells, recognized by the receptor NKG2D. Ligands to this receptor (NKG2D-L) are membrane-bound but can also be shed and released in soluble form. (3) NK cells express the enzyme heparanase (HPSE) to degrade heparin sulfate proteoglycans, allowing them to migrate in the tumor tissue. NK cells' secretion of IFNγ induces the production of fibronectin 1 (FN1) by tumor cells, further remodeling the ECM. (4) NK cells modulate angiogenesis by releasing VEGF, PIGF and IL-8. VEGF secretion can be repressed by STAT5 or by soluble VEGF receptor (sVEGFR1) induced as a response to hypoxia. Tumor cells' secretion of TGFβ induces the conversion of NK cells into ILC1-like cells expressing CD49a and CD69, and exhibiting anti-tumor cytotoxic activity. Plasticity within the ILC family also includes the conversion from ILC2 to ILC1, and from ILC3 to ILC1, both induced by IL-12 and reversed by IL-4 and IL-23, respectively. ILC2s have a pro-tumorigenic role via secretion of IL-13 driving the expansion of myeloid-derived suppressor cells (MDSCs), and an anti-tumorigenic role through IL-5 mediated recruitment of eosinophils and activation of B cells. ILC3 can also stimulate antibody production by B cells, and can favor leukocyte recruitment to the TME when sensing IL-12, through IFNγ-mediated upregulation of ICAM-1 and VCAM-1. They may also play a role in angiogenesis through the production of IL-17. NCR+ILC3s and LTis accumulate in tertiary lymphoid structures (TLS) and may also promote lymphangiogenesis. Finally, both ILC2 and ILC3 express MHC class II and were able to prime CD4 T cells in vitro.