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.

NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high anti-tumor activity against colorectal cancer / J. Mikulak, F. Oriolo, E. Bruni, A. Roberto, F.S. Colombo, A. Villa, M. Bosticardo, I. Bortolomai, E. Lo Presti, S. Meraviglia, F. Dieli, S. Vetrano, S. Danese, S. Della Bella, M.M. Carvello, M. Sacchi, G. Cugini, G. Colombo, M. Klinger, P. Spaggiari, M. Roncalli, I. Prinz, S. Ravens, B. di Lorenzo, E. Marcenaro, B. Silva-Santos, A. Spinelli, D. Mavilio. - In: JCI INSIGHT. - ISSN 2379-3708. - 4:24(2019 Dec).

NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high anti-tumor activity against colorectal cancer

J. Mikulak
Primo
;
F. Oriolo
Secondo
;
F.S. Colombo;S. Vetrano;S. Della Bella
Membro del Collaboration Group
;
G. Colombo;M. Klinger;M. Roncalli;A. Spinelli
Penultimo
;
D. Mavilio
Ultimo
2019

Abstract

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.
Colorectal cancer; Gastroenterology; Immunology; Innate immunity; T cells
Settore MED/46 - Scienze Tecniche di Medicina di Laboratorio
Settore MED/04 - Patologia Generale
Settore MED/12 - Gastroenterologia
Settore MED/06 - Oncologia Medica
5-nov-2019
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/688376
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