The expanding role of innate lymphoid cells and their T-cell counterparts in gastrointestinal cancers
Introduction
The innate immune system is our first line of defense against pathogens. The main cellular components of the innate immune response include macrophages, monocytes, neutrophils, natural killer cells (NK) and their relatives, innate lymphoid cells (ILCs). The second arm of our defense system is governed by the adaptive immune response, which consists of B lymphocytes and T lymphocytes, including both CD4+ T-helper (Th) cells and CD8+ cytotoxic T-cells. In a number of solid tumor types, neoplastic cells can hijack the natural function of both the innate and adaptive immune system to avoid destruction and fuel their growth (Grivennikov et al., 2010, Pardoll, 2012).
At the onset of tumorigenesis, when cell intrinsic tumor suppressor mechanisms have failed, the innate immune system activates a cascade of events that are designed to eradicate neoplastic cells. In the initial response, the immune surveillance governed by sub-types of macrophages and other tissue resident immune cells results in either the direct destruction of a neoplastic cell, or the production of chemokines to attract additional innate immune cells, including NK cells that can directly lyse the tumor cells (Georgoudaki et al., 2016, Dahlberg et al., 2015). In the second phase of immune surveillance, dendritic cells (DCs) bridge the innate and adaptive immune response by collecting tumor antigens and presenting them to naïve T-cells, resulting in the activation of cytotoxic CD8+ T-cells that complete tumor destruction (Palucka and Banchereau, 2012).
Over the past 10 years, it has become clear that tumor cells have devised mechanisms to overcome immune editing, and hijack the effector functions of both innate and adaptive immune cells. Here we will discuss recent literature for two previously under-characterized immune cell populations, ILCs and CD4+ Th17 cells, both of which are present in the tumor microenvironment. We will review our current understanding of how ILCs, in particular the ILC3 subgroup, inadvertently contribute to the initiation and progression of gastrointestinal (GI) cancers and compare this to our knowledge of the overlapping function of Th17 cells. We focus on GI cancers, as these cell types are critical in host defense to infections and the control of chronic inflammation, both of which increase the risk of colorectal cancer (CRC) development (Kim and Chang, 2014, Dejea et al., 2013).
Section snippets
Innate lymphoid cells are primarily localized to mucosal surfaces
The GI tract contains the largest concentration of immune cells in the body. Sheltered by the mucosal barrier, an immune response can be triggered by exposure to ingested antigens, chemical irritants, and dysregulation of commensal bacteria. In a thought provoking review of ‘The Hallmarks of Cancer’, Hanahan and Weinberg discuss our emerging scientific appreciation of the extrinsic tumor-suppressive role the immune system can play, with disruption of the normal immune function capable of
Our current understanding of the function of ILCs in the gastrointestinal mucosa
ILCs are subdivided into three groups, based on their known transcription factor and cytokine profiles (Spits et al., 2013). This sub-classification parallels the descriptors for their adaptive Th-cell counterparts (Fig. 1). In contrast to Th-cells, ILCs can respond rapidly to cytokines present in the microenvironment without the need for specific antigens, providing an immediate outlet for tissue defense systems against pathogens, maintenance of epithelial homeostasis, and repair at mucosal
Link between innate lymphoid cells and the progression of gastrointestinal cancers
It is now well appreciated that the growth and progression of cancers of the GI tract can be fueled by cytokines produced within the tumor microenvironment. It is clear from the overlap in localization, transcriptional activity, cytokine profiles and effector functions that ILCs strongly resemble different Th-cell subsets. Here we will summarize our understanding of the role of ILCs in GI cancers, and how they, together with their Th counterparts, may inadvertently aid tumor growth.
Is the evolutionary redundancy of ILC3s and Th17 cells hijacked by tumor cells?
The similarities between ILCs and their Th-cell counterparts leaves one to question when they arose during evolution, if they co-evolved to ensure robust immunity, or if selective pressure led to shared cytokine expression signatures that tumors use to their advantage. The substantial heterogeneity of both the ILC3 and Th17 lineages suggests that they may still be evolving under pressure from a changing microbial environment.
Implications for the success and failures of cancer therapeutics
Pending the stage of CRC at the time of diagnosis, patients will undergo standard-of-care chemotherapeutic treatments. It is now appreciated that chemotherapy drastically alters the microbial environment (Roy and Trinchieri, 2017), which would indirectly alter the ILC and Th17 profiles of a patient. As a result of their location, ILCs would be the first population of cells to respond to chemotherapy induced changes to a microbial environment, in particular ILC3s, which would result in an
Concluding remarks
Our understanding of the role of ILCs in the tumor microenvironment is only just beginning, with the relative contribution of ILC3s and Th17 cells to tumor progression not clear. ILCs are unique in that they do not need antigen sensing for their activation, and thus respond to environmental triggers more rapidly than T-cells. This distinctive feature also suggests that they may be the first to trigger the growth and progression of a tumor, which may be sustained by their adaptive T-cell
Acknowledgements
The laboratory of TP is supported by Victorian State Government Operational Infrastructure Support and the National Health and Medical Research Council Australia (NHMRC) project grants APP1080498, and APP1098643, and Worldwide Cancer Research project grant no. 14-1197. PMN was supported by an Australian Postgraduate Scholarship and TP is a Victorian Cancer Agency Fellow, and a WEHI Centenary Fellow.
References (118)
- et al.
Interleukin-12 and −23 Control Plasticity of CD127(+) Group 1 and Group 3 Innate Lymphoid Cells in the Intestinal Lamina Propria
Immunity
(2015) - et al.
Interleukin-23 is sufficient to induce rapid de novo gut tumorigenesis independent of carcinogens, through activation of innate lymphoid cells
Mucosal Immunol.
(2014) - et al.
Intraepithelial type 1 innate lymphoid cells are a unique subset of IL-12- and IL-15-responsive IFN-gamma-producing cells
Immunity
(2013) - et al.
Interferon Receptor Signaling Pathways Regulating PD-L1 and PD-L2 Expression
Cell Rep.
(2017) - et al.
Reprogramming Tumor-Associated Macrophages by Antibody Targeting Inhibits Cancer Progression and Metastasis
Cell Rep.
(2016) - et al.
RORgammat(+) innate lymphoid cells acquire a proinflammatory program upon engagement of the activating receptor NKp44
Immunity
(2013) - et al.
IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer
Cancer Cell
(2009) - et al.
Immunity, inflammation, and cancer
Cell
(2010) - et al.
Induction of innate lymphoid cell-derived interleukin-22 by the transcription factor STAT3 mediates protection against intestinal infection
Immunity
(2014) - et al.
Hallmarks of cancer: the next generation
Cell
(2011)