Crosstalk between Innate Lymphoid Cells and Other Immune Cells in the Tumor Microenvironment
The role of ILC3 in tumor development. Studies in microbe-induced intestinal cancer have provided evidence of the protumor role of ILC3. (a)(i) The expression of CXCR6 allows ILC3 to migrate in response to the CXCL13 gradient and localize in gut microenvironments where they respond to DC-derived IL-23. Upon activation, ILC3 secrete IL-17 and IL-22, which contribute to the inflammatory environment that supports tumor development by inducing proliferation of epithelial cells in a STAT-3-mediated mechanism. The control of IL-22 activity by a soluble receptor, IL-22BP, is important to maintain a fine balance that dictates proliferation and tissue repair or tumor development. Highlighting the importance of crosstalk between ILC and other immune cells, gut macrophages (a)(ii) activated by microbial signals produce the proinflammatory cytokine IL-1, which targets and induces RORt+ ILC to secrete GM-CSF required to maintain Treg and macrophages. The action of these three cell types creates a tolerant environment that results in tumor progression. Another potential mechanism that might operate in cancer involves monocytes (a)(iii), which produce TNF-α following stimulation by microbial signals. The proinflammatory monocytes increase the frequency of IL-17-producing ILC3 and as part of the functional circuit IL-17 acts upon monocytes to increase their microbicidal activity. It would be interesting to evaluate whether this functional circuit results in increased tumoricidal activity by inflammatory monocytes. In subcutaneous melanoma, tumor-derived IL-12 activates NKp46+LTi, which induce the tumor microvasculature to express increased levels of ICAM and VCAM. The increased expression of these adhesion molecules allows the infiltration of CD4+ and CD8+, which mediate tumor suppression. Panel (a)(i) diagram is based on .
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