TY - JOUR
T1 - NKp46-expressing human gut-resident intraepithelial Vδ1 T cell subpopulation exhibits high anti-tumor activity against colorectal cancer
AU - Lo Presti, Elena
AU - Dieli, Francesco
AU - Meraviglia, Serena
AU - Bortolomai, Ileana
AU - Carvello, Michele M.
AU - Ravens, Sarina
AU - Villa, Anna
AU - Sacchi, Matteo
AU - Roberto, Alessandra
AU - Spaggiari, Paola
AU - Di Lorenzo, Biagio
AU - Cugini, Giovanni
AU - Colombo, Giovanni
AU - Oriolo, Ferdinando
AU - Bruni, Elena
AU - Danese, Silvio
AU - Klinger, Marco
AU - Bella, Silvia Della
AU - Carvello, Michele M.
AU - Bella, Silvia Della
AU - Silva-Santos, Bruno
AU - Bosticardo, Marita
AU - Mikulak, Joanna
AU - Prinz, Immo
AU - Vetrano, Stefania
AU - Mavilio, Domenico
AU - Marcenaro, Emanuela
AU - Danese, Silvio
AU - Roncalli, Massimo
AU - Colombo, Federico S.
AU - Spinelli, Antonino
AU - Klinger, Marco
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - http://hdl.handle.net/10447/387479
M3 - Article
VL - 4
SP - 1
EP - 42
JO - JCI insight
JF - JCI insight
SN - 2379-3708
ER -