The IL-23R and Its Genetic Variants: A Hitherto Unforeseen Bridge Between the Immune System and Cancer Development

Abstract

IL-23R (interleukin-23 receptor), found on the surface of several immune cells, plays a key role in the immune system. Indeed, this process is not limited to the inflammatory response but also plays a role in the adaptive immune response. The binding between IL-23R and its specific ligand, the interleukin 23, initiates a number of specific signals by modulating both properties and behavior of immune cells. In particular, it is critical for the regulation of T helper 17 cells (Th17). Th17s are a subset of T cells involved in autoimmune and inflammatory diseases, as well as in cancer. The clinical relevance of IL-23R is underscored by its association with an elevated susceptibility or diminished vulnerability to a spectrum of diseases, including psoriasis, ankylosing spondylitis, and inflammatory bowel disease (IBD). Evidence has emerged that suggests it may also serve to predict both tumor progression and therapeutic responsiveness. It is noteworthy that the IL-23/IL-23R pathway is emerging as a promising therapeutic target. A number of biologic drugs, such as monoclonal antibodies, are currently developing with the aim of blocking this interaction, thus reducing inflammation. This represents a significant advancement in the field of medicine, offering new hope for pursuing more effective and personalized treatments. Recent studies have also investigated the role of such a pathway in autoimmune diseases, and its potential impact on infections as well as in carcinogenesis. The aim of this review is to focus on the role of IL-23R in immune genetics and its potential for modulating the natural history of neoplastic disease.

Keywords: IL-23R; Th17; genetic variants; immune cells; tumor microenvironment.

Figure 3

Major IL-23R-related variants in tumors and expression of IL-23R in single cells and in the T-cell lineage. The main IL-23R variants are expressed and distributed in a tumor-dependent manner. All cancers affect both genders. Breast cancer is an exception. The top panel right shows the expression of the transcript on cell types. The bottom panel right shows the relative expression of the transcript in the T lineage. Both images are freely adapted from the Human Protein Atlas. Created in Biorender. www.biorender.com/ (accessed on 20 December 2024).

Figure 4

3D structure of IL-23R and pathological pathways involved in IL-23R downstream signaling in cancers. (A) shows the 3D structure of the IL-23R protein, with the positions of the major missense variants along the amino acid chain highlighted, according to the Alphafold database. (B) shows the main pathways that have been studied so far and are involved downstream of IL-23/IL-23R signaling in the above-mentioned cancers. Created in Biorender. www.biorender.com/ (accessed on 22 November 2024).

Figure 1

Structure of IL-23R. (A). Chromosomal gene mapping, correlated transcription, variants position between exons and introns according to ClinVar, GnomAD and Ensembl. The protein structure is shown below, adapted from the human protein atlas. The main domains are annotated as they are organized in the protein structure: HPA056427 (antigenically recognized domain); MDM and MDSP (trans-membrane portion and localization signal); LC-reg (low complexity region); IP-reg (immunoglobulin-like fold domains and fibronectin III superfamily domains). (B). Graphical representation of the major alternative splicing forms of the IL-23R gene by distribution frequency, with gene location and structure. The variants described have been extracted from ensembl.org. Created in BioRender. www.biorender.com/ (accessed on 22 November 2024).

Figure 2

Signaling by IL-23R. Some of the main producers of IL-23 are endothelial cells, macrophages, dendritic cells and neutrophils. Pathways are started when the two subunits of IL-23, p19 and p40, bind to IL-23R and IL-12Rβ1. This activates Tyk2 and Jak2. Tyk2 and Jak2 mainly promote STAT, NF-κB, SGK1, RORγt, Satb1 and Blimp1 and related down-stream effectors. Created in BioRender. www.biorender.com/ (accessed on 20 December 2024).

Figure 5

Key approved pharmacological agents for the IL-23R pathway. The figure illustrates the principal authorized pharmacological agents that interfere with IL-23R or its downstream effectors and impede the IL-23R signaling pathway. Created in BioRender. www.biorender.com/ (accessed on 20 December 2024).