{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T16:00:42Z","timestamp":1767974442039,"version":"3.49.0"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T00:00:00Z","timestamp":1707091200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The pro-inflammatory cytokine interleukin-23 (IL-23) has been implicated in colorectal cancer (CRC). Yet, the cell-specific contributions of IL-23 receptor (IL-23R) signaling in CRC remain unknown. One of the cell types that highly expresses IL-23R are colonic regulatory T cells (Treg cells). The aim of this study was to define the contribution of Treg cell-specific IL-23R signaling in sporadic and inflammation-associated CRC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In mice, the role of IL-23R in Treg cells in colitis-associated cancer (CAC) was investigated using azoxymethane\/dextran sodium sulphate in wild-type Treg cell reporter mice (WT, <jats:italic>Foxp3<\/jats:italic><jats:sup>YFP-iCre<\/jats:sup>), and mice harboring a Treg cell-specific deletion of IL-23 (<jats:italic>Il23r<\/jats:italic><jats:sup>\u0394Treg<\/jats:sup>). The role of IL-23R signaling in Treg cells in sporadic CRC was examined utilizing orthotopic injection of the syngeneic colon cancer cell line MC-38 submucosally into the colon\/rectum of mice. The function of macrophages was studied using clodronate. Finally, single-cell RNA-seq of a previously published dataset in human sporadic cancer was reanalyzed to corroborate these findings.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In CAC, <jats:italic>Il23r<\/jats:italic><jats:sup>\u0394Treg<\/jats:sup> mice had increased tumor size and increased dysplasia compared to WT mice that was associated with decreased tumor-infiltrating macrophages. In the sporadic cancer model, <jats:italic>Il23r<\/jats:italic><jats:sup>\u0394Treg<\/jats:sup> mice had increased survival and decreased tumor size compared to WT mice. Additionally, MC-38 tumors of <jats:italic>Il23r<\/jats:italic><jats:sup>\u0394Treg<\/jats:sup> mice exhibited a higher frequency of pro-inflammatory macrophages and IL-17 producing CD4<jats:sup>+<\/jats:sup> T cells. The decreased tumor size in <jats:italic>Il23r<\/jats:italic><jats:sup>\u0394Treg<\/jats:sup> mice was macrophage-dependent. These data suggest that loss of IL-23R signaling in Treg cells permits IL-17 production by CD4<jats:sup>+<\/jats:sup> T cells that in turn promotes pro-inflammatory macrophages to clear tumors. Finally, analysis of TCGA data and single-cell RNA-seq analysis of a previously published dataset in human sporadic cancer, revealed that <jats:italic>IL23R<\/jats:italic> was highly expressed in CRC compared to other cancers and specifically in tumor-associated Treg cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Inflammation in colorectal carcinogenesis differs with respect to the contribution of IL-23R signaling in regulatory T cells.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fonc.2023.1276743","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T23:13:37Z","timestamp":1707174817000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Distinct roles for interleukin-23 receptor signaling in regulatory T cells in sporadic and inflammation-associated carcinogenesis"],"prefix":"10.3389","volume":"13","author":[{"given":"Justin","family":"Jacobse","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer M.","family":"Pilat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel E.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron","family":"Kwag","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew A.","family":"Buendia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yash A.","family":"Choksi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Kay","family":"Washington","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher S.","family":"Williams","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas O.","family":"Markham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah P.","family":"Short","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeremy A.","family":"Goettel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2024,2,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1136\/gut.48.4.526","article-title":"The risk of colorectal cancer in ulcerative colitis: A meta-analysis","volume":"48","author":"Eaden","year":"2001","journal-title":"Gut"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1097\/MEG.0000000000000891","article-title":"Chronic comorbidities associated with inflammatory bowel disease: Prevalence and impact on healthcare costs in Switzerland","volume":"29","author":"B\u00e4hler","year":"2017","journal-title":"Eur J Gastroenterol Hepatol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199011013231802","article-title":"Ulcerative colitis and colorectal cancer","volume":"323","author":"Ekbom","year":"1990","journal-title":"New Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/S1471-4914(01)02194-3","article-title":"Inflammation and colorectal cancer: IBD-associated and sporadic cancer compared","volume":"8","author":"Rhodes","year":"2002","journal-title":"Trends Mol Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-42986-1","article-title":"Immunoprofiling of colitis-associated and sporadic colorectal cancer and its clinical significance","volume":"9","author":"Soh","year":"2019","journal-title":"Sci Rep"},{"key":"B6","first-page":"994","article-title":"Safety of ustekinumab in inflammatory bowel disease: pooled safety analysis of results from phase 2\/3 studies","volume-title":"Inflammatory bowel diseases","author":"Sandborn","year":"2021"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa9420","article-title":"Individual intestinal symbionts induce a distinct population of ROR\u03b3+ regulatory T cells","volume":"349","author":"Sefik","year":"2015","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.903564","article-title":"Colorectal cancer-infiltrating regulatory T cells: functional heterogeneity, metabolic adaptation, and therapeutic targeting","volume":"13","author":"Aristin Revilla","year":"2022","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2200757119","DOI":"10.1073\/pnas","article-title":"Antibody-mediated blockade of the IL23 receptor destabilizes intratumoral regulatory T cells and enhances immunotherapy","volume":"119","author":"Wight","year":"2022","journal-title":"PNAS"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112128","article-title":"Interleukin-23 receptor signaling impairs the stability and function of colonic regulatory T cells","volume":"42","author":"Jacobse","year":"2023","journal-title":"Cell Rep"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2250348","DOI":"10.1002\/eji.202250348","article-title":"Interleukin 23 receptor: Expression and regulation in immune cells","author":"Mezghiche","year":"2023","journal-title":"Eur J Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/ni1539","article-title":"TGF-\u03b2 and IL-6 drive the production of IL-17 and IL-10 by T cells and restrain TH-17 cell-mediated pathology","volume":"8","author":"McGeachy","year":"2007","journal-title":"Nat Immunol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"6540","DOI":"10.1038\/s41388-021-02046-3","article-title":"CCL11 exacerbates colitis and inflammation-associated colon tumorigenesis","volume":"40","author":"Polosukhina","year":"2021","journal-title":"Oncogene"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00044","article-title":"Defective IL-23\/IL-17 axis protects p47phox-\/- mice from colon cancer","volume":"8","author":"Richter","year":"2017","journal-title":"Front Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1286850","article-title":"Heterogeneity of tertiary lymphoid structures in cancer","volume":"14","author":"You","year":"2023","journal-title":"Front Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.5a0614-311r","article-title":"Olfactomedin-4 autoantibodies give unusual c-ANCA staining patterns with reactivity to a subpopulation of neutrophils","volume":"97","author":"Amirbeagi","year":"2015","journal-title":"J Leukoc Biol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2016.58","article-title":"Olfactomedin 4 deletion induces colon adenocarcinoma in ApcMin\/+ mice","volume":"35","author":"Liu","year":"2016","journal-title":"Oncogene"},{"key":"B18","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1080\/2162402X.2016.1189052","article-title":"Stromal CCR6 drives tumor growth in a murine transplantable colon cancer through recruitment of tumor-promoting macrophages","volume":"5","author":"Nandi","year":"2016","journal-title":"Oncoimmunology"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41597-019-0131-5","article-title":"Deep single-cell RNA sequencing data of individual T cells from treatment-na\u00efve colorectal cancer patients","volume":"6","author":"Zhang","year":"2019","journal-title":"Sci Data"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3384","article-title":"Inflammatory networks underlying colorectal cancer","volume":"17","author":"Lasry","year":"2016","journal-title":"Nat Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a028530","article-title":"Interleukin (IL)-12 and IL-23 and their conflicting roles in cancer","volume":"10","author":"Yan","year":"2018","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"536","DOI":"10.1016\/j.ccr.2010.11.004","article-title":"Regulation of the IL-23 and IL-12 balance by stat3 signaling in the tumor microenvironment","volume":"18","author":"Kortylewski","year":"2010","journal-title":"Cancer Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.10.021","article-title":"Transcriptional landscape of human tissue lymphocytes unveils uniqueness of tumor-infiltrating T regulatory cells","volume":"45","author":"De Simone","year":"2016","journal-title":"Immunity"},{"key":"B24","doi-asserted-by":"crossref","unstructured":"Obata-NinomiyaK\n            DeS\n            CarrionJ\n            HuA\n            ZieglerSF\n          Emerging role for thymic stromal lymphopoietin-responsive regulatory T cells in colorectal cancer progression in humans and mice2022","DOI":"10.1126\/scitranslmed.abl6960"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.642285","article-title":"Mechanisms of macrophage plasticity in the tumor environment: manipulating activation state to improve outcomes","volume":"12","author":"Ricketts","year":"2021","journal-title":"Front Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22168470","article-title":"Tumor-associated macrophages (Tams) in colorectal cancer (crc): From mechanism to therapy and prognosis","volume":"22","author":"Wang","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201141737","article-title":"Macrophages participate in IL-17-mediated inflammation","volume":"42","author":"Barin","year":"2012","journal-title":"Eur J Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"5015","DOI":"10.1016\/j.cell.2021.07.029","article-title":"Dysregulation of ILC3s unleashes progression and immunotherapy resistance in colon cancer","volume":"184","author":"Goc","year":"2021","journal-title":"Cell"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/nature11465","article-title":"Adenoma-linked barrier defects and microbial products drive IL-23\/IL-17-mediated tumour growth","volume":"491","author":"Grivennikov","year":"2012","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1152\/ajpgi.00358.2013.-Individuals","article-title":"Inducible loss of one Apc allele in Lrig1-expressing progenitor cells results in multiple distal colonic tumors with features of familial adenomatous polyposis","volume":"307","author":"Powell","year":"2014","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.3836","article-title":"In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis","volume":"35","author":"Roper","year":"2017","journal-title":"Nat Biotechnol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/laban.254","article-title":"Estimation of rat mammary tumor volume using caliper and ultrasonography measurements","volume":"42","author":"Faustino-Rocha","year":"2013","journal-title":"Lab Anim (NY)"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pbio.2000531","article-title":"The yin and yang of memory consolidation: hippocampal and neocortical","volume":"15","author":"Genzel","year":"2017","journal-title":"PloS Biol"},{"key":"B34","unstructured":"SubramanianA\n            TamayoP\n            MoothaVK\n            MukherjeeS\n            EbertBL\n            GilletteMA\n          Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles2005"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-017-1349-1","article-title":"xCell: Digitally portraying the tissue cellular heterogeneity landscape","volume":"18","author":"Aran","year":"2017","journal-title":"Genome Biol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2011.07.050","article-title":"Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett\u2019s epithelium","volume":"141","author":"Sato","year":"2011","journal-title":"Gastroenterology"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.neo.2017.05.002","article-title":"UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses","volume":"19","author":"Chandrashekar","year":"2017","journal-title":"Neoplasia (United States)"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/nature11252","article-title":"Comprehensive molecular characterization of human colon and rectal cancer","volume":"487","author":"Muzny","year":"2012","journal-title":"Nature"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2023.10.002","article-title":"A synthesis and subgroup analysis of the eosinophilic esophagitis tissue transcriptome","author":"Jacobse","year":"2023","journal-title":"J Allergy Clin Immunol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1276743\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T23:13:44Z","timestamp":1707174824000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2023.1276743\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,5]]},"references-count":39,"alternative-id":["10.3389\/fonc.2023.1276743"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2023.1276743","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,5]]},"article-number":"1276743"}}