Investigation of IL-23 (p19, p40) and IL-23R identifies nuclear expression of IL-23 p19 as a favorable prognostic factor in colorectal cancer: a retrospective multicenter study of 675 patients

Abstract

IL-23 is a heterodimeric cytokine involved in inflammatory diseases; its role in cancer progression is controversial. Here we analyse the expression of IL-23 subunits (p40 and p19) and IL-23R in colorectal cancer with regard to disease progression, clinical-pathological and molecular aspects. Immunohistochemistry for IL-23p19, IL-23p40, IL-23R and CD8 was performed on a multi-punch tissue microarray of 195 colorectal cancers (cohort 1), matched normal tissue, adenoma and lymph node metastases. Results were compared with clinical-pathological features and CD8+ T-cell counts, then validated on two patient cohorts (cohort 2: n=341, cohort 3: n=139). Cytoplasmic/membranous expression of IL-23 (p19 and p40 subunits) and IL-23R, respectively were over-expressed in carcinomas versus adenomas and normal tissues (p<0.0001) but were reduced in lymph node metastases (p<0.0001). Nuclear IL-23p19 expression was observed in 23.1% and was associated with early TNM stage (p=0.0186), absence of venous (p=0.0124) and lymphatic invasion (p=0.01493), favorable survival (p=0.014) and absence of distant metastasis (p=0.0146; specificity: 100%). This unexpected cellular localization was confirmed by cell fractionation. The beneficial effect of nuclear IL-23p19 was restricted to tumours with CD8+ high counts. Results were validated on Cohorts 2/3. This multicenter study underlines the possible CD8+ dependency and beneficial effect of nuclear IL-23p19 on overall patient survival.

Increased expression of interleukin‐23 associated with progression of colorectal cancer

“…In uni-and multivariate analysis, high IL-23 expression was associated with poor survival. This result was consistent with the finding of increased IL-23 expression in the normal-carcinoma sequence [13][14][15] and suggested IL-23 expression as a prognostic predictor.…”

Immune mediator expression signatures are associated with improved outcome in ovarian carcinoma

“…Both IL-23 and CXCL-13 may facilitate pro-tumor phenotypes through initiating tumorigenesis, increasing angiogenesis, 41 promoting metastasis 42 and reducing infiltration of CD8 + T cells 43 in colorectal and non-small cell lung carcinoma (NSCLC), and by maintaining self-renewability of ovarian cancer stem cells (OCSCs) within the tumor microenvironment. 44 In our analyses, we found a significant correlation between higher expression of the Th17 differentiation cytokine IL-23 with better OS, in line with a study by Wolf et al 45 We also found that higher expression of the chemokine CXCL-13 was also associated with better OS in our cohort.…”

IL-23, rather than IL-17, is crucial for the development of ovalbumin-induced allergic rhinitis

“…IL-23 has also been shown to enhance the expression of IL-17, by either in vitro generated human Th17 or ex vivo isolated memory Th17 cells, whereas IL-23 also exerts an inhibitory effect on the IL-12-induced IFN-␥ responses in Th1 cells (Annunziato et al, 2007). Additionally, accumulating evidences suggest that both IL-23 and IL-17 are significantly upregulated in many tumors, such as hepatocellular carcinoma, non-small cell lung cancer, and colorectal cancer (Helbling et al, 2014;Xu et al, 2014;Zarogoulidis et al, 2014). Further, it has been reported that IL-23 signaling promotes tumor growth and progression, and development of a tumoral IL-17 response (Grivennikov et al, 2012).…”

“…Allergic rhinitis, which is a condition similar to common cold, could affect mental and learning capacities up to 30% (Global Allergy and Asthma European Network addresses the allergy and asthma epidemic) (Bousquet et al, 2009). AR is an inflammatory disease of the nasal mucosa induced by an immunoglobulin E (Helbling et al, 2014)-mediated reaction in allergen-sensitized individuals. It has been reported that numerous loci and candidate genes show an association with AR (Gaddam et al, 2012;Genuneit et al, 2009;Ibrahim et al, 2012;Tomazic et al, 2014).…”