6533b82ffe1ef96bd12946e3
RESEARCH PRODUCT
NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high antitumor activity against colorectal cancer
Marco KlingerStefania VetranoBiagio Di LorenzoMichele CarvelloAnna VillaMarita BosticardoSilvio DaneseMassimo RoncalliFrancesco DieliAntonino SpinelliElena BruniIleana BortolomaiAlessandra RobertoMatteo SacchiBruno Silva-santosImmo PrinzFederico ColomboFerdinando OrioloElena Lo PrestiPaola SpaggiariGiovanni CuginiEmanuela MarcenaroGiovanni ColomboJoanna MikulakSarina RavensSerena MeravigliaDomenico MavilioSilvia Della Bellasubject
0301 basic medicineMaleColorectal cancerImmunotherapy AdoptiveMice0302 clinical medicineSex Hormone-Binding GlobulinCytotoxic T cellAntigens LyIntestinal MucosaIntraepithelial LymphocytesInnate immunityAged 80 and overGastroenterologyAge FactorsReceptors Antigen T-Cell gamma-deltaGeneral MedicineMiddle AgedPhenotypemedicine.anatomical_structure030220 oncology & carcinogenesisDisease ProgressionFemaleColorectal NeoplasmsResearch ArticleAdultColonT cellImmunologyT cellsBiologydigestive systemColorectal cancer; Gastroenterology; Immunology; Innate immunity; T cells03 medical and health sciencesYoung AdultIleummedicineAnimalsHumansAgedNeoplasm StagingTumor microenvironmentInnate immune systemNatural Cytotoxicity Triggering Receptor 1medicine.diseaseColorectal cancer030104 developmental biologyCancer researchIntraepithelial lymphocyteHoming (hematopoietic)T-Lymphocytes Cytotoxicdescription
γδ T cells account for a large fraction of human intestinal intraepithelial lymphocytes (IELs) endowed with potent anti-tumor activities. However, little is known about their origin, phenotype and clinical relevance in colorectal cancer (CRC). To determine γδ IEL gut-specificity, homing and functions, γδ T cells were purified from human healthy blood, lymph nodes, liver, skin, intestine either disease-free or affected by CRC or generated from thymic precursors. The constitutive expression of NKp46 specifically identifies a new subset of cytotoxic Vδ1 T cells representing the largest fraction of gut-resident IELs. The ontogeny and gut-tropism of NKp46pos/Vδ1 IELs depends both on distinctive features of Vδ1 thymic precursors and gut-environmental factors. Either the constitutive presence of NKp46 on tissue-resident Vδ1 intestinal IELs or its induced-expression on IL-2/IL-15 activated Vδ1 thymocytes are associated with anti-tumor functions. Higher frequencies of NKp46pos/Vδ1 IELs in tumor-free specimens from CRC patients correlate with a lower risk of developing metastatic III/IV disease stages. Additionally, our in vitro settings reproducing CRC tumor-microenvironment inhibited the expansion of NKp46pos/Vδ1 cells from activated thymic precursors. These results parallel the very low frequencies of NKp46pos/Vδ1 IELs able to infiltrate CRC, thus providing new insights to either follow-up cancer progression or develop novel adoptive cellular therapies.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2019-12-19 |