NKp46-expressing human gut-resident intraepithelial V?1 T cell subpopulation exhibits high antitumor activity against colorectal cancer.

ABSTRACT: ?? T cells account for a large fraction of human intestinal intraepithelial lymphocytes (IELs) endowed with potent antitumor activities. However, little is known about their origin, phenotype, and clinical relevance in colorectal cancer (CRC). To determine ?? IEL gut specificity, homing, and functions, ?? T cells were purified from human healthy blood, lymph nodes, liver, skin, and intestine, either disease-free, affected by CRC, or generated from thymic precursors. The constitutive expression of NKp46 specifically identifies a subset of cytotoxic V?1 T cells representing the largest fraction of gut-resident IELs. The ontogeny and gut-tropism of NKp46+/V?1 IELs depends both on distinctive features of V?1 thymic precursors and gut-environmental factors. Either the constitutive presence of NKp46 on tissue-resident V?1 intestinal IELs or its induced expression on IL-2/IL-15-activated V?1 thymocytes are associated with antitumor functions. Higher frequencies of NKp46+/V?1 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 NKp46+/V?1 cells from activated thymic precursors. These results parallel the very low frequencies of NKp46+/V?1 IELs able to infiltrate CRC, thus providing insights to either follow-up cancer progression or to develop adoptive cellular therapies.

SUBMITTER: Mikulak J 

PROVIDER: S-EPMC6975269 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature