Elsevier

Molecular Immunology

Volume 110, June 2019, Pages 48-56
Molecular Immunology

The expanding role of innate lymphoid cells and their T-cell counterparts in gastrointestinal cancers

https://doi.org/10.1016/j.molimm.2017.11.013Get rights and content

Highlights

  • ILC and Th17 cell populations are enriched at mucosal surfaces.

  • IL-17 and IL-22 are signature ILC3 and Th17 cytokines.

  • IL-17 and IL-22 are implicated in colorectal cancer progression.

  • The relative contribution of ILC and Th17-type cytokines to cancer needs to be defined.

Abstract

Innate lymphoid cells (ILCs) contribute to the regulation of gastrointestinal (GI) homeostasis. Over the past 15 years, there has been a large effort to dissect the mechanisms required for GI homeostasis, with a major focus on different immune cell populations and the cytokines that they produce. In contrast to T-helper (Th) cells, ILCs respond rapidly to cytokines in their microenvironment in the absence of specific antigens; however, once activated both cell populations have similar effector functions. Two effector cytokines produced by both ILC3 and Th17 cell populations, Interleukin (IL)-17 and IL-22, have taken center stage for their ability to signal directly to GI epithelial cells and promote epithelial cell survival. In this review, we outline our current understanding of ILCs in the GI tract, and focus on GI cancers associated with aberrant production of IL-17 and IL-22. We highlight evidence from both mouse and patient-based analyses and discuss how tumor cells may hijack the potential evolutionary redundancy of these two cell populations.

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.

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