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  • Review Article
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Emerging cytokine networks in colorectal cancer

Key Points

  • Cytokine networks are key aspects of tumour immunology, particularly for colorectal cancer (CRC), for which inflammation and antitumour immunity are critical determinants of disease progression.

  • Interleukin-6 (IL-6) and tumour necrosis factor (TNF) have been studied extensively in CRC and other malignancies and are drivers of signal transducer and activator of transcription 3 (STAT3) and nuclear factor-κB (NF-κB) pathways, respectively. These cytokines promote malignant progression by enhancing proliferation, invasiveness and resistance to apoptosis.

  • Studies in both humans and animal models have revealed new players in CRC initiation and progression. Many of these cytokines (IL-17A, IL-22, transforming growth factor-β (TGFβ) and granulocyte–macrophage colony-stimulating factor (GM-CSF)) are necessary for damage repair but are also oncogenic in certain settings.

  • Several adaptations that allow CRC cells to maximize the benefits that they receive from immune interaction have recently been identified: mutations in TP53 (which encodes p53) enhance IL-6 and TNF signalling; oncogenic KRAS mutations enhance resistance to pro-apoptotic TGFβ signalling; and suppressors of pro-inflammatory signalling such as SOCS3 can be epigenetically silenced.

  • The pro-tumorigenic or antitumorigenic effects of individual cytokines are context dependent and heavily influenced by synergisms in the complex cytokine milieu. STAT3–NF-κB crosstalk is critical for CRC and can be driven by a number of cytokines with similar biochemical functions.

  • IL-6 neutralization was unsuccessful in a clinical trial in patients with CRC and is one of the few examples of clinical trials using cytokine-modulatory approaches for CRC. The multitude of pro-tumorigenic cytokines with a role in CRC suggests that the following strategies may enhance therapeutic potential relative to single cytokine blockade: broad-spectrum targeting of receptors shared by several cytokines; combinatorial therapies targeting multiple distinct cytokine pathways; small-molecule inhibitors of cytokine signalling pathways; and/or careful patient stratification based on molecular oncology features to tailor the right immunomodulatory therapies to the right patients.

Abstract

Cytokine networks are crucial aspects of tumour immunology, particularly for colorectal cancer (CRC), in which inflammation and antitumour immunity are key determinants of disease progression. In this Review, we highlight new insights into the functions of well-known cytokines in CRC, describe recently discovered roles for a growing number of novel players, and emphasize the complexity and therapeutic implications of the cytokine milieu. We also discuss how cancer mutations and epigenetic adaptations influence the oncogenic potential of cytokines, a relatively unexplored area that could yield crucial insights into tumour immunology and facilitate the effective application of cytokine-modulatory therapies for CRC.

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Figure 1: The double-edged sword of inflammation in colorectal cancer.
Figure 2: Cytokines in the pathogenesis of colorectal cancer.
Figure 3: Adaptive mechanisms of cytokine exploitation in colorectal cancer.
Figure 4: Cytokine signalling in colorectal cancer — opportunities for therapeutic intervention.

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Acknowledgements

The authors gratefully acknowledge funding support from the Wellcome Trust (Senior Investigator Award) and the European Research Council (ERC Advance Grant). N.R.W. is supported by an Irvington postdoctoral fellowship from the Cancer Research Institute. S.M. and F.F. are respectively supported by doctoral scholarships from the Rhodes Trust and Cancer Research UK.

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Glossary

Checkpoint blockade immunotherapy

A therapeutic intervention (typically a monoclonal antibody) designed to block inhibitory 'checkpoint' signals that suppress or terminate immune activity, with the intention of enhancing or inducing antitumour immunity. Notable checkpoint targets include cytotoxic T lymphocyte antigen 4 (CTLA4), programmed cell death protein 1 (PD1) and PD1 ligand 1 (PDL1).

Mismatch repair

(MMR). A DNA repair pathway that recognizes and corrects mismatched base pairs (typically those that arise from errors of chromosomal DNA replication). There are two main types of MMR components: MutS homologues (MSH1–MSH6) and MutL homologues (PMS1, PMS2 and MLH1).

Epithelial to mesenchymal transition

(EMT). A reversal of the mesenchymal to epithelial transition that occurs during development. EMT or the de-differentiation of epithelial cells can have normal physiological roles (such as in wound healing) or can be associated with fibrotic pathologies and cancer.

WNT-β-catenin pathway

A signalling pathway that regulates cell fate determination, proliferation, adhesion, migration and polarity during development. In addition, WNT proteins and their downstream signalling molecules have been implicated in tumorigenesis and have causative roles in human colorectal cancers. WNT signalling activates TCF–LEF family transcription factors by stabilizing their co-activator, β-catenin, and mobilizing this factor from the cytoplasm to the nucleus. Adenomatous polyposis coli protein (APC), the most commonly inactivated protein in colorectal cancer, is a negative regulator of this signalling pathway.

Stemness

An imprecise term referring to the possession of qualities normally found in stem cells, such as the capacity for self-renewal.

Microsatellite instability

(MSI). A DNA hypermutation process that is indicative of defects in DNA mismatch repair. MSI is detectable as differences in the number of repeats in microsatellite loci relative to the repeat number found in the inherited genome.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous group of myeloid cells related to macrophages, granulocytes and dendritic cells. These cells are produced in response to various inflammatory and/or tumour-derived cytokines and are thought to inhibit tumour-specific immune responses.

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West, N., McCuaig, S., Franchini, F. et al. Emerging cytokine networks in colorectal cancer. Nat Rev Immunol 15, 615–629 (2015). https://doi.org/10.1038/nri3896

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