title: 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.
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Melina
authors.initials: M
authors.lastname: Helbling
authors.forename: Anne
authors.initials: A
authors.lastname: Lukesch
authors.forename: Aladin
authors.initials: A
authors.lastname: Haimovici
authors.forename: Eva
authors.initials: E
authors.lastname: Karamitopoulou
authors.forename: Martin D
authors.initials: MD
authors.lastname: Berger
authors.forename: Marion
authors.initials: M
authors.lastname: Hädrich
authors.forename: Makhmud
authors.initials: M
authors.lastname: Mallaev
authors.forename: Beat
authors.initials: B
authors.lastname: Schnüriger
authors.forename: Viktor H
authors.initials: VH
authors.lastname: Koelzer
authors.forename: Heather
authors.initials: H
authors.lastname: Dawson
authors.forename: Markus
authors.initials: M
authors.lastname: Borner
authors.forename: Rupert
authors.initials: R
authors.lastname: Langer
authors.forename: Robert
authors.initials: R
authors.lastname: Rosenberg
authors.forename: Ulrich
authors.initials: U
authors.lastname: Nitsche
authors.forename: Daniel
authors.initials: D
authors.lastname: Inderbitzin
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lugli
authors.forename: Mario
authors.initials: M
authors.lastname: Tschan
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Inti
authors.initials: I
authors.lastname: Zlobec
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003593:Cytoplasm / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism*; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D018123:Receptors, Interleukin / Q000378:metabolism*; D012189:Retrospective Studies; D046888:Tissue Array Analysis
chemical_list: C515500:IL23R protein, human; D053762:Interleukin-12 Subunit p40; D053760:Interleukin-23 Subunit p19; D018123:Receptors, Interleukin