Pleiotropic Role and Bidirectional Immunomodulation of Innate Lymphoid Cells in Cancer

Abstract

Innate lymphoid cells (ILCs) are largely tissue resident and respond rapidly toward the environmental signals from surrounding tissues and other immune cells. The pleiotropic function of ILCs in diverse contexts underpins its importance in the innate arm of immune system in human health and disease. ILCs derive from common lymphoid progenitors but lack adaptive antigen receptors and functionally act as the innate counterpart to T-cell subsets. The classification of different subtypes is based on their distinct transcription factor requirement for development as well as signature cytokines that they produce. The discovery and subsequent characterization of ILCs over the past decade have mainly focused on the regulation of inflammation, tissue remodeling, and homeostasis, whereas the understanding of the multiple roles and mechanisms of ILCs in cancer is still limited. Emerging evidence of the potent immunomodulatory properties of ILCs in early host defense signifies a major advance in the use of ILCs as promising targets in cancer immunotherapy. In this review, we will decipher the non-exclusive roles of ILCs associated with both protumor and antitumor activities. We will also dissect the heterogeneity, plasticity, genetic evidence, and dysregulation in different cancer contexts, providing a comprehensive understanding of the complexity and diversity. These will have implications for the therapeutic targeting in cancer.

Keywords: ILCs; cancer; heterogenity; immunosurveillance; immunothearpy; plasticicity; tumor immune microenvironment.

Figure 1

Innate lymphoid cell lineage and classification. Innate lymphoid cells (ILCs) derive from common lymphoid progenitors (CLPs) and give rise to common innate lymphoid progenitors (CILPs) and common helper innate lymphoid progenitors (CHILPs). CILPs differentiate into natural killer (NK) cell progenitors (NKPs) and then terminally differentiate into NK cells. CHILPs divide into innate lymphoid cell progenitors (ILCPs) and lymphoid tissue inducer progenitors (LTiPs), which generate all helper-like ILC subsets, ILC1s, ILC2s, ILC3s, and LTis, respectively. The transcriptional repressor Id2 is developmentally required and sequentially expressed in the ILC precursors. Id2-dependent precursors can further differentiate with lineage-specific transcription factors. Recent studies suggest that Zbtb16⁺ILCPs harbored extensive NK and/or ILC precursors potential, indicating a revised model for ILC differentiation. The different ILC subsets need their unique transcription factors for development and secretion of their signature cytokines in response to different stimulators, which mirror the phenotype and the function of adaptive helper T cells, Th1, Th2, and Th17, respectively.

Figure 2

Innate lymphoid cells (ILCs) and extracellular matrix (ECM) remodeling. Activated ILC interactions with ECM in tumor immune microenvironment (TIME) conclusively affect the consequences of tumor progression. Interferon-gamma (IFNγ) secreted by natural killer (NK) cells stimulate tumor cells to express FN1 that causes ECM remodeling resulting in the inhibition of tumor metastasis. Mutually, FN1 stabilizes NK cell survival and facilitates NK cell migration through the induction of B-cell leukemia 2 (Bcl-2) expression. In response to IL-12, ILC1s upregulate several cytokines and chemokines, such as IFNγ, CXCR6, CCR5, CXCR3, and CCR1, to recruit ILC3s to the tumor site, thus causing ECM remodeling and tumor growth repression. Through ECM remodeling, adipose ILC1s contribute to adipose tissue fibrogenesis. Similarly, in mouse liver, IL-33-activated ILC2s release IL-13 to stimulate hepatic stellate cells to produce ECM proteins, thus inducing liver fibrogenesis. Moreover, tumor cells recruit CCL21 to activate LTis, whereby causing tumor stromal reorganization and facilitation of lymph node metastasis.

Figure 3

Innate lymphoid cells (ILCs) in tumor angiogenesis. ILCs act as tumor angiogenesis modulators by releasing pro-angiogenic factors and by inducing the recruitment and infiltration of immune cells to affect tumor-related inflammation. Transforming growth factor-beta (TGF-β) secreted by tumor cells activate natural killer (NK) cell to produce vascular endothelial growth factor (VEGF) and placenta growth factor (PIG) to induce tumor angiogenesis; conversely, the transcription factor STAT5 represses the expression of VEGF resulting in the inhibition of angiogenesis and tumor growth. ILC1s produce two signature cytokines, interferon-gamma (IFNγ) and tumor necrosis factor-alpha (TNFα), that are associated with cell proliferation and angiogenesis. TNFα secreted by ILC1s increases vascular cell adhesion molecule (VCAM)1 expression causing tumor vascular formation, whereas in a different context, TNFα-producing ILC1s can either destroy tumor vasculature or induce apoptosis acting as antitumor effectors. Furthermore, IFNγ released from ILC1s causes STAT1 activation, thereby inhibiting angiogenesis formation. ILC2s respond to IL-33 and induce angiogenesis and vascular permeability through ST2 receptor binding. IL-17 and IL-22 released by ILC3s promote angiogenesis via stimulation of vascular endothelia cell migration and cord formation. The indirect role of ILC3s in tumor angiogenesis is also shown in the recruitment of myeloid-derived suppressor cells (MDSCs), regulatory T cell (Treg) cells, and the promotion of M2-like macrophages in the tumor immune microenvironment (TIME).

Figure 4

Innate lymphoid cells (ILCs) modulate adaptive immunity by direct or indirect interactions with other cells in the tissue. ILC2s functionally resemble Th2 cells and play a critical role in the type 2 immune response. The role of ILC2s in the establishment of an by direct interactions with Th2 cells through OX40L/OX40 under IL-33 stimulation or through indirect interactions by the section of IL-13 or amphiregulin (AREG), which then causes regulatory T cell (Treg) cell expansion and myeloid-derived suppressor cell (MDSC) activation. ILC2-derived IL-13 also stimulates dendritic cell (DC) recruitment and CCL17 production to provoke a Th2 response. ILC2s produce IL-4 to regulate Th2 differentiation, which may suggest a potential role in promoting tumor growth and metastasis. In terms of antitumor function, the release of IL-5 and IL-9 by ILC2s restrains tumor growth through eosinophils recruitment and activation and DC antigen presentation. Conversely, high expression of IL-9 is associated with T-cell transformation in humans, indicating that the anti-apoptotic properties on transformed cells promote tumorigenesis. ILC3s are important in the Th17 immune response. The direct interactions with CD4⁺T cells are either through MHC II/TCR or through OX40/OX40 and CD30L/CD30 to regulate T-cell survival or B-cell class switch, respectively. ILC3 migrate to the draining mesenteric lymph node to initiate an adaptive response that requires CCR7 expression. ILC3s promote IgA production in a T cell-dependent manner via the regulation of CD4⁺T-cell homing by sLTα3 secretion and also in a T cell-independent manner via control of B-cell homing by the release of LTα1β2. ILC3-derived IL-22 triggers epithelial serum amyloid A protein (SAA) production to induce local Th17 response in a STAT3-dependent manner. The secretion of IL-22 and GM-CSF by ILC3 stimulates macrophages and DCs to release IL-10, and this consequently results in regulatory T cell (Treg) cell expansion. In addition, IL-1β produced by macrophages activates ILC3 and leads to CD4⁺T-cell priming, whereas T cell-derived cytokines also cross-regulate ILC response, indicating the bidirectional interactions between ILC3 and T cell-mediated immunity.

Figure 5

The plasticity between innate lymphoid cell (ILC) subsets. Mature ILCs display substantial plasticity depending on the distinct cytokines, the microenvironment milieus, and the diverse context of cancer. Natural killer (NK) cells convert into non-cytotoxic ILC1s upon transforming growth factor-beta (TGF-β) stimulation in the tumor microenvironment (TME) in mouse fibrosarcoma and melanoma. NK cells also convert into ILC3s in response to IL-1β, preventing stage 3 NK cells from stage 4 mature NK cells and retaining ILC3-like phenotype. ILC1s show plasticity toward all other ILCs subtypes, including NK cells, ILC2s, and ILC3s with the absence of TGF-β, the accumulation of IL-4, and under the stimulation of IL-23, respectively. Conversion of ILC2s to ILC1s needs IL-1β, whereas ILC2s in response to IL-25 differentiate into IL-17-producing ILC3s. ILC3 treatment with IL-15 and IL-12 leads to NK cell conversion, whereas plasticity from ILC3s toward ILC1s and ILC2s depends on IL-23, IL-12, and IL-2/TLR2 signals. NCR⁻ILC3 and NCR⁺ILC3 conversion needs Notch and TGF-β signals, indicating the bidirectional plasticity of ILC3s in the face of different challenges.