Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Oct 3:13:981479.
doi: 10.3389/fimmu.2022.981479. eCollection 2022.

Emerging roles for IL-25 and IL-33 in colorectal cancer tumorigenesis

Eric Jou  1 , Noe Rodriguez-Rodriguez  1 , Andrew N J McKenzie  1
Affiliations
Review

Emerging roles for IL-25 and IL-33 in colorectal cancer tumorigenesis

Eric Jou et al. Front Immunol. .

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, and is largely refractory to current immunotherapeutic interventions. The lack of efficacy of existing cancer immunotherapies in CRC reflects the complex nature of the unique intestinal immune environment, which serves to maintain barrier integrity against pathogens and harmful environmental stimuli while sustaining host-microbe symbiosis during homeostasis. With their expression by barrier epithelial cells, the cytokines interleukin-25 (IL-25) and IL-33 play key roles in intestinal immune responses, and have been associated with inappropriate allergic reactions, autoimmune diseases and cancer pathology. Studies in the past decade have begun to uncover the important roles of IL-25 and IL-33 in shaping the CRC tumour immune microenvironment, where they may promote or inhibit tumorigenesis depending on the specific CRC subtype. Notably, both IL-25 and IL-33 have been shown to act on group 2 innate lymphoid cells (ILC2s), but can also stimulate an array of other innate and adaptive immune cell types. Though sometimes their functions can overlap they can also produce distinct phenotypes dependent on the differential distribution of their receptor expression. Furthermore, both IL-25 and IL-33 modulate pathways previously known to contribute to CRC tumorigenesis, including angiogenesis, tumour stemness, invasion and metastasis. Here, we review our current understanding of IL-25 and IL-33 in CRC tumorigenesis, with specific focus on dissecting their individual function in the context of distinct subtypes of CRC, and the potential prospects for targeting these pathways in CRC immunotherapy.

Keywords: IL-25; IL-33; colorectal cancer; cytokine; microenvironment; mouse model.

PubMed Disclaimer

Conflict of interest statement

ANJM is on the scientific advisory board of SinoMab. ANJM developed antibodies against IL-25R which MRC has licenced to SinoMab. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Overview of the IL-25 and IL-33 signalling pathways. Figure depicts the IL-25 (left) and IL-33 (right) signalling pathways. Act1, CIKS; c-Jun N-terminal kinase, JNK.
Figure 2
Figure 2
Overview of CRC development and Wnt signaling pathway. (A) CRC development is associated with a gradual accumulation of genetic alterations involving the loss of tumour suppressors (purple) or gain of oncogenic function (red). Loss of the tumour suppressor adenomatous polyposis coli (APC) facilitates the initial transition from normal epithelium to adenomas. Patient age when the driver genes are commonly mutated are also shown (66). Ras, rat sarcoma virus; TGF-β, transforming growth factor-β; p53, tumour protein p53; PI3K, phosphatidylinositol 3-kinase. (B) The destruction complex, consisting of APC, AXIN, casein kinase 1α (CK1α) and glycogen synthase kinase 3β (GSK3β), induces the continuous degradation of β-catenin in the absence of Wnt signaling. The destruction complex is disassembled when Wnt ligand binds to its receptor frizzled and coreceptor lipoprotein receptor-related protein 5 or 6 (LRP5 or LRP6 respectively), or when APC is mutated, leading to the accumulation and nuclear translocation of β-catenin, and downstream Wnt signaling (67). DVL, dishevelled; TCF/LEF, T cell factor/lymphoid enhancer factor.
Figure 3
Figure 3
Overview of IL-25 in APC-mutation-mediated CRC and colitis-associated cancer (CAC) models. Figure depicts the immune-regulatory role of IL-25 characterised in preclinical models of APC-mutation-mediated CRC (A) and CAC (B). (A) In the intestinal tumour microenvironment, DCLK1+ tuft-like cells are the main source of IL-25, and the latter may in turn promote tumour stemness. IL-25 activates tumour IL-25R+ ILC2s to produce IL-4 and IL-13, which increases arginase 1 (Arg1) expression in tumour M-MDSCs leading to enhanced M-MDSC suppressive capacity. M-MDSC-mediated T cell suppression reduces T cell proliferation and IFNγ production, leading to impaired anti-tumour immunity and tumour progression. (B) In the AOM/DSS model of CAC, IL-25 reduces tumour burden through eosinophils. This may be via ILC2-derived IL-5 or other yet-to-be identified factors promoting eosinophil activation and cytotoxicity against tumours in a CD8+ T cell-independent manner. Conversely, IL-25 may act in an autoparacrine manner to promote tumour stemness characterised by upregulation of stem markers Lgr5, CD133 and DCLK1 downstream IL-25 signaling in a Hedgehog pathway-dependent manner.
Figure 4
Figure 4
Overview of IL-33 in APC-mutation-mediated CRC and colitis-associated cancer (CAC) models. Figure depicts the role of IL-33 in preclinical models of APC-mutation-mediated CRC (A) and CAC (B). (A) In APC-mutation-mediated CRC models, IL-33 is proposed to promote tumorigenesis through activating ST2+ Tregs and mast cells which may have pro-tumoral properties through suppressing anti-tumour T cells and production of IL-4 respectively. (B) In AOM/DSS-mediated models of CAC, IL-33 can similarly promote tumorigenesis through ST2+ Tregs, but also via direct action on ST2+ epithelial tumour cells compromising the intestinal barrier resulting in colitis and CAC. Conversely, IL-33 may inhibit CAC through sustaining intestinal barrier integrity via stimulating B cells to produce IgA, and also via direct activation of anti-tumoral eosinophils.
Figure 5
Figure 5
Mechanisms of MDSC-mediated T cell suppression. Immunosuppression of effector T cells by MDSCs occurs through multiple mechanisms. MDSC-derived nitric oxide (NO) and reactive oxygen species (ROS) inhibit T cell effector function and promote apoptosis. MDSCs can also suppress effector T cells through amino acid depletion MDSCs express arginase 1 (Arg1) and indoleamine-pyrrole 2,3-dioxygenase (IDO), which deplete the amino acids L-arginine and L-tryptophan respectively in the tumour microenvironment. Metabolic suppression of T cells ensues as these amino acids are essential for T cell effector function. In addition, MDSCs express programmed death-ligand 1 (PD-L1), which interacts with its receptor programmed cell death protein 1 (PD-1) on T cells, resulting in T cell functional exhaustion. Finally, MDSC-derived transforming growth factor-β (TGF-β) converts T cells to a regulatory phenotype (Tregs). NOS, nitric oxide synthase.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer J Clin (2018) 68(6):394–424. doi: 10.3322/caac.21492 - DOI - PubMed
    1. Arnold M, Sierra MS, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global patterns and trends in colorectal cancer incidence and mortality. Gut (2017) 66(4):683–91. doi: 10.1136/gutjnl-2015-310912 - DOI - PubMed
    1. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell (1990) 61(5):759–67. doi: 10.1016/0092-8674(90)90186-i - DOI - PubMed
    1. Overman MJ, Ernstoff MS, Morse MA. Where we stand with immunotherapy in colorectal cancer: Deficient mismatch repair, proficient mismatch repair, and toxicity management. Am Soc Clin Oncol Educ Book (2018) 38:239–47. doi: 10.1200/edbk_200821 - DOI - PubMed
    1. Munkholm P. Review article: The incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther (2003) 18 Suppl 2:1–5. doi: 10.1046/j.1365-2036.18.s2.2.x - DOI - PubMed

Publication types