{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:51:52Z","timestamp":1790790712011,"version":"4.1.0"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T00:00:00Z","timestamp":1689638400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003762","name":"Institut Pasteur","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003762","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004099","name":"Ligue Contre le Cancer","doi-asserted-by":"publisher","award":["Equipe Labellisee Ligue 2018"],"award-info":[{"award-number":["Equipe Labellisee Ligue 2018"]}],"id":[{"id":"10.13039\/501100004099","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001677","name":"Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001677","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Familial adenomatous polyposis (FAP) is an inherited disease characterized by the development of large number of colorectal adenomas with high risk of evolving into colorectal tumors. Mutations of the <jats:italic>Adenomatous polyposis coli (APC)<\/jats:italic> gene is often at the origin of this disease, as well as of a high percentage of spontaneous colorectal tumors. <jats:italic>APC<\/jats:italic> is therefore considered a tumor suppressor gene. While the role of <jats:italic>APC<\/jats:italic> in intestinal epithelium homeostasis is well characterized, its importance in immune responses remains ill defined. Our recent work indicates that the APC protein is involved in various phases of both CD4 and CD8 T cells responses. This prompted us to investigate an array of immune cell features in FAP subjects carrying <jats:italic>APC<\/jats:italic> mutations. A group of 12 FAP subjects and age and sex-matched healthy controls were studied. We characterized the immune cell repertoire in peripheral blood and the capacity of immune cells to respond <jats:italic>ex vivo<\/jats:italic> to different stimuli either in whole blood or in purified T cells. A variety of experimental approaches were used, including, pultiparamater flow cytometry, NanosString gene expression profiling, Multiplex and regular ELISA, confocal microscopy and computer-based image analyis methods. We found that the percentage of several T and natural killer (NK) cell populations, the expression of several genes induced upon innate or adaptive immune stimulation and the production of several cytokines and chemokines was different. Moreover, the capacity of T cells to migrate in response to chemokine was consistently altered. Finally, immunological synapses between FAP cytotoxic T cells and tumor target cells were more poorly structured. Our findings of this pilot study suggest that mild but multiple immune cell dysfunctions, together with intestinal epithelial dysplasia in FAP subjects, may facilitate the long-term polyposis and colorectal tumor development. Although at an initial discovery phase due to the limited sample size of this rare disease cohort, our findings open new perspectives to consider immune cell abnormalities into polyposis pathology.<\/jats:p>","DOI":"10.3389\/fimmu.2023.1163466","type":"journal-article","created":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T14:20:04Z","timestamp":1689690004000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":12,"title":["T cell migration and effector function differences in familial adenomatous polyposis patients with APC gene mutations"],"prefix":"10.3389","volume":"14","author":[{"given":"C\u00e9line","family":"Cuche","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Mastrogiovanni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Juzans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9l\u00e8ne","family":"Laude","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-No\u00eblle","family":"Ungeheuer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Krentzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Isabella","family":"Gariboldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Scott-Algara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Madec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Goyard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Floch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ga\u00eblle","family":"Chauveau-Le Friec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierre","family":"Lafaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte","family":"Renaudat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muriel","family":"Le Bidan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Micallef","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Schmutz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Mella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie","family":"Novault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Hasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darragh","family":"Duffy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Di Bartolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9s","family":"Alcover","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"95","DOI":"10.2147\/TACG.S51484","article-title":"The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management","volume":"8","author":"Leoz","year":"2015","journal-title":"Appl Clin Genet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.100479","article-title":"Interactions and functions of the adenomatous polyposis coli (Apc) protein at a glance","volume":"126","author":"Nelson","year":"2013","journal-title":"J Cell Sci"},{"key":"B3","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1016\/j.biochi.2018.11.003","article-title":"Role of adenomatous polyposis coli (Apc) gene mutations in the pathogenesis of colorectal cancer; current status and perspectives","volume":"157","author":"Aghabozorgi","year":"2019","journal-title":"Biochimie"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.05.042","article-title":"Apc is an rna-binding protein, and its interactome provides a link to neural development and microtubule assembly","volume":"158","author":"Preitner","year":"2014","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-18-1154","article-title":"Identification of endogenous adenomatous polyposis coli interaction partners and beta-Catenin-Independent targets by proteomics","volume":"17","author":"Popow","year":"2019","journal-title":"Mol Cancer Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.bj.2021.10.002","article-title":"Cell polarity regulators, multifunctional organizers of lymphocyte activation and function","volume":"45","author":"Mastrogiovanni","year":"2022","journal-title":"BioMed J"},{"key":"B7","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1007\/978-1-4419-1145-2_3","article-title":"Apc in cell migration","volume":"656","author":"Etienne-Manneville","year":"2009","journal-title":"Adv Exp Med Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201206010","article-title":"Apc binds intermediate filaments and is required for their reorganization during cell migration","volume":"200","author":"Sakamoto","year":"2013","journal-title":"J Cell Biol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201001016","article-title":"Adenomatous polyposis coli protein nucleates actin assembly and synergizes with the formin Mdia1","volume":"189","author":"Okada","year":"2010","journal-title":"J Cell Biol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2004.10.017","article-title":"Interaction with Iqgap1 links apc to Rac1, Cdc42, and actin filaments during cell polarization and migration","volume":"7","author":"Watanabe","year":"2004","journal-title":"Dev Cell"},{"key":"B11","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.cell.2020.03.001","article-title":"The emerging landscape of immune cell therapies","volume":"181","author":"Weber","year":"2020","journal-title":"Cell"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2020.02.022","article-title":"Turning cold into hot: firing up the tumor microenvironment","volume":"6","author":"Duan","year":"2020","journal-title":"Trends Cancer"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1126\/science.1129139","article-title":"Type, density, and location of immune cells within human colorectal tumors predict clinical outcome","volume":"313","author":"Galon","year":"2006","journal-title":"Science"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)30789-X","article-title":"International validation of the consensus immunoscore for the classification of colon cancer: a prognostic and accuracy study","volume":"391","author":"Pages","year":"2018","journal-title":"Lancet"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.09.020","article-title":"Adenomatous polyposis coli defines treg differentiation and anti-inflammatory function through microtubule-mediated nfat localization","volume":"21","author":"Aguera-Gonzalez","year":"2017","journal-title":"Cell Rep"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/immunohorizons.2000044","article-title":"Adenomatous polyposis coli modulates actin and microtubule cytoskeleton at the immunological synapse to tune ctl functions","volume":"4","author":"Juzans","year":"2020","journal-title":"Immunohorizons"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abl5942","article-title":"The tumor suppressor adenomatous polyposis coli regulates T lymphocyte migration","volume":"8","author":"Mastrogiovanni","year":"2022","journal-title":"Sci Adv"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-0304","article-title":"T-Regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis","volume":"69","author":"Gounaris","year":"2009","journal-title":"Cancer Res"},{"key":"B19","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.jconrel.2016.09.019","article-title":"Camelid single-domain antibodies: a versatile tool for in vivo imaging of extracellular and intracellular brain targets","volume":"243","author":"Li","year":"2016","journal-title":"J Control Release"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/all.14365","article-title":"A highly sensitive bioluminescent method for measuring allergen-specific ige in microliter samples","volume":"75","author":"Goyard","year":"2020","journal-title":"Allergy"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2014.03.002","article-title":"Functional analysis Via standardized whole-blood stimulation systems defines the boundaries of a healthy immune response to complex stimuli","volume":"40","author":"Duffy","year":"2014","journal-title":"Immunity"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat Methods"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1109\/TSMC.1979.4310076","article-title":"A threshold selection method from Gray-level histograms","volume":"9","author":"Otsu","year":"1979","journal-title":"IEEE Trans Systems Man Cybernetics"},{"key":"B24","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1007\/978-3-319-28549-8_3","article-title":"Transforms and operators for directional bioimage analysis: a survey","volume":"219","author":"Puspoki","year":"2016","journal-title":"Adv Anat Embryol Cell Biol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/0146-664X(82)90034-X","article-title":"Elliptic Fourier features of a closed contour","volume":"18","author":"Kuhl","year":"1982","journal-title":"Comput Graphics Image Process"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2017.00235","article-title":"Microglia morphological categorization in a rat model of neuroinflammation by hierarchical cluster and principal components analysis","volume":"11","author":"Fernandez-Arjona","year":"2017","journal-title":"Front Cell Neurosci"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.868164","article-title":"Development and external validation of a simple-to-Use dynamic nomogram for predicting breast malignancy based on ultrasound morphometric features: a retrospective multicenter study","volume":"12","author":"Zhang","year":"2022","journal-title":"Front Oncol"},{"key":"B28","article-title":"Analyse d\u2019image geometrique et morphometrique par diagrammes de forme et voisinages adaptatifs generaux","volume-title":"PhD Thesis Ecole nationale superieure des mines de saint etienne France","author":"Rivollier","year":"2010"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22539","article-title":"The umd-apc database, a model of nation-wide knowledge base: update with data from 3,581 variations","volume":"35","author":"Grandval","year":"2014","journal-title":"Hum Mutat"},{"key":"B30","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.3390\/cells9092125","article-title":"Transcriptional regulation of Wnt\/Beta-catenin pathway in colorectal cancer","volume":"9","author":"Bian","year":"2020","journal-title":"Cells"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/s0959-8049(02)00040-0","article-title":"The apc gene in colorectal cancer","volume":"38","author":"Fodde","year":"2002","journal-title":"Eur J Cancer"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1710751114","article-title":"Cortical actin recovery at the immunological synapse leads to termination of lytic granule secretion in cytotoxic T lymphocytes","volume":"114","author":"Ritter","year":"2017","journal-title":"Proc Natl Acad Sci U.S.A."},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.04.013","article-title":"Actin depletion initiates events leading to granule secretion at the immunological synapse","volume":"42","author":"Ritter","year":"2015","journal-title":"Immunity"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.591348","article-title":"Coordinating cytoskeleton and molecular traffic in T cell migration, activation, and effector functions","volume":"8","author":"Mastrogiovanni","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.exphem.2004.05.027","article-title":"Antitumor response of Cd14+\/Cd16+ monocyte subpopulation","volume":"32","author":"Szaflarska","year":"2004","journal-title":"Exp Hematol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.08.002","article-title":"Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors","volume":"8","author":"De Palma","year":"2005","journal-title":"Cancer Cell"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2010.04200.x","article-title":"Circulating Cd14(+) Cd16(+) monocyte levels predict tissue invasive character of cholangiocarcinoma","volume":"161","author":"Subimerb","year":"2010","journal-title":"Clin Exp Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2021.03.001","article-title":"Icosl in host defense at epithelial barriers: lessons from icoslg deficiency","volume":"72","author":"Roussel","year":"2021","journal-title":"Curr Opin Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2023.102283","article-title":"Immune checkpoint receptors in autoimmunity","volume":"80","author":"Burke","year":"2023","journal-title":"Curr Opin Immunol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0065-2776(05)88001-0","article-title":"Cd22: a multifunctional receptor that regulates b lymphocyte survival and signal transduction","volume":"88","author":"Tedder","year":"2005","journal-title":"Adv Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/nri798","article-title":"T-Cell development and the Cd4-Cd8 lineage decision","volume":"2","author":"Germain","year":"2002","journal-title":"Nat Rev Immunol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.163.11.5954","article-title":"The cxc chemokine stromal cell-derived factor activates a gi-coupled phosphoinositide 3-kinase in T lymphocytes","volume":"163","author":"Sotsios","year":"1999","journal-title":"J Immunol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2018.00322","article-title":"Plasticity of type I interferon-mediated responses in cancer therapy: from anti-tumor immunity to resistance","volume":"8","author":"Budhwani","year":"2018","journal-title":"Front Oncol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.cell.2016.08.069","article-title":"Loss of ifn-gamma pathway genes in tumor cells as a mechanism of resistance to anti-Ctla-4 therapy","volume":"167","author":"Gao","year":"2016","journal-title":"Cell"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1313474110","article-title":"Syntaxin binding mechanism and disease-causing mutations in Munc18-2","volume":"110","author":"Hackmann","year":"2013","journal-title":"Proc Natl Acad Sci U.S.A."}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1163466\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,18]],"date-time":"2023-07-18T14:20:08Z","timestamp":1689690008000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1163466\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,18]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2023.1163466"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1163466","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,18]]},"article-number":"1163466"}}