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 / Mikulak, Joanna; Oriolo, Ferdinando; Bruni, Elena; Roberto, Alessandra; Colombo, Federico S; Villa, Anna; Bosticardo, Marita; Bortolomai, Ileana; Lo Presti, Elena; Meraviglia, Serena; Dieli, Francesco; Vetrano, Stefania; Danese, Silvio; Della Bella, Silvia; Carvello, Michele M; Sacchi, Matteo; Cugini, Giovanni; Colombo, Giovanni; Klinger, Marco; Spaggiari, Paola; Roncalli, Massimo; Prinz, Immo; Ravens, Sarina; di Lorenzo, Biagio; Marcenaro, Emanuela; Silva-Santos, Bruno; Spinelli, Antonino; Mavilio, Domenico. - In: JCI INSIGHT. - ISSN 2379-3708. - 4:24(2019). [10.1172/jci.insight.125884]

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

Danese, Silvio;
2019-01-01

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.
2019
Colorectal cancer
Gastroenterology
Immunology
Innate immunity
T cells
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/119497
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