Crosstalk between Innate Lymphoid Cells and Other Immune Cells in the Tumor Microenvironment

Abstract

Our knowledge and understanding of the tumor microenvironment (TME) have been recently expanded with the recognition of the important role of innate lymphoid cells (ILC). Three different groups of ILC have been described based on their ability to produce cytokines that mediate the interactions between innate and adaptive immune cells in a variety of immune responses in infection, allergy, and autoimmunity. However, recent evidence from experimental models and clinical studies has demonstrated that ILC contribute to the mechanisms that generate suppressive or tolerant environments that allow tumor regression or progression. Defining the complex network of interactions and crosstalk of ILC with other immune cells and understanding the specific contributions of each type of ILC leading to tumor development will allow the manipulation of their function and will be important to develop new interventions and therapeutic strategies.

Figure 1

Antitumor activities of group 1 innate lymphoid cells (ILC1). Upon tumor development dendritic cells (DC) are activated and secrete IL-12, which activates ILC1. ILC1 respond to stimulation secreting IFN-γ and TNF-α, which target and activate different cell types within the tumor microenvironment that display antitumor activities. These cell types include NK cells that kill tumor cells through mechanisms involving perforin and granzyme secretion. CD4⁺ T cells provide costimulation (through cell to cell interactions and secretion of soluble factors) and priming of CD8⁺ cytotoxic T cells which display antitumor cytotoxic activities. IFN-γ secreted by ILC1 inhibits the differentiation of tumor-infiltrating macrophages into M2 macrophages providing a mechanism that prevents secretion of vascular endothelial growth factor (VGEF) and tumor angiogenesis. Due to cell plasticity ILC3 can differentiate into ILC within the tumor microenvironment and contribute to the anti- and protumor responses.

Figure 2

Anti- and protumor activities of group 2 innate lymphoid cells (ILC2). (a) The antitumor activity of ILC2 has been demonstrated in a model of lung metastatic melanoma. IL-33-activated ILC2 produce IL-5, which induces the recruitment and maintenance of eosinophils that display antitumorigenic activity. In contrast, ILC2 can also play an important role in tumor progression as shown in models of liver and breast cancer (b). A study in the 4T1 syngeneic model of breast cancer has shown that IL-33 produced by tumor cells is associated with the induction of a protumor environment characterized by increased numbers of MDSC and Treg. Contributing to the suppressive environment, an increased number of ILC2 secrete IL-5/IL-13 and target MDSC, which in turn secrete TGFβ (to activate and maintain Treg) and arginase (Arg) to inhibit natural killer (NK) cell activity. Under these immunosuppressive conditions, 4T1 tumors develop and metastasize. (c) Further, evidence of the dual role of ILC2 in tumor development has been highlighted by studies in models of liver cancer. Cell damage of epithelial cells lining the bile ducts (cholangiocytes) in the presence of IL-33-activated ILC2 leads to secretion of IL-13, which under normal conditions is used by epithelial cells to proliferate and induce tissue repair. However, under conditions of oncogenic priming (activation of protumor signaling pathways) the control of epithelial cells proliferation is lost and leads to tumor development.

Figure 3

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 RORγt⁺ 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 Ly6^hi 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 [35].