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

gamma delta 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 gamma delta IEL gut specificity, homing, and functions, gamma delta 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 delta 1T cells representing the largest fraction of gut-resident IELs. The ontogeny and gut-tropism of NKp46(+)/V delta 1IELs depends both on distinctive features of V delta 1 thymic precursors and gut-environmental factors. Either the constitutive presence of NKp46 on tissue-resident Vd1 intestinal IELs or its induced expression on IL-2/IL-15-activated V delta 1 thymocytes are associated with antitumor functions. Higher frequencies of NKp46(+)/V delta 1IELs 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 delta 1 cells from activated thymic precursors. These results parallel the very low frequencies of NKp46+/V delta 1 IELs able to infiltrate CRC, thus providing insights to either follow-up cancer progression or to develop adoptive cellular therapies.