Human intestinal and circulating invariant natural killer T cells are cytotoxic against colorectal cancer cells via the perforin–granzyme pathway. Issue 12 (21st October 2021)

• Record Type: Journal Article
• Authors: Díaz‐Basabe, Angélica; Burrello, Claudia; Lattanzi, Georgia; Botti, Fiorenzo; Carrara, Alberto; Cassinotti, Elisa; Caprioli, Flavio; Facciotti, Federica
• Is Part Of: Molecular oncology. Volume 15:Issue 12(2021)
• Page Start: 3385
• Page End: 3403
• Publication Date: 2021-10-21
• Subjects: CD1d -- colorectal cancer -- cytotoxicity -- iNKT -- perforin; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.13104
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : Invariant natural killer T (iNKT) cells are lipid‐specific T lymphocytes endowed with cytotoxic activities and are thus considered important in antitumor immunity. While several studies have demonstrated iNKT cell cytotoxicity against different tumors, very little is known about their cell‐killing activities in human colorectal cancer (CRC). Our aim was to assess whether human iNKT cells are cytotoxic against colon cancer cells and the mechanisms underlying this activity. For this purpose, we generated stable iNKT cell lines from peripheral blood and colon specimens and used NK‐92 and peripheral blood natural killer cells as cell‐mediated cytotoxicity controls. In vitro cytotoxicity was assessed using a panel of well‐characterized human CRC cell lines, and the cellular requirements for iNKT cell cytotoxic functions were evaluated. We demonstrated that both intestinal and circulating iNKT cells were cytotoxic against the entire panel of CRC lines, as well as against freshly isolated patient‐derived colonic epithelial cancer cells. Perforin and/or granzyme inhibition impaired iNKT cell cytotoxicity, whereas T‐cell receptor (TCR) signaling was a less stringent requirement for efficient killing. This study is the first evidence of tissue‐derived iNKT cell cytotoxic activity in humans, as it shows that iNKT cells depend on the perforin–granzyme pathway and both adaptive and innate signal recognition for proper elimination of colon cancer cells. Abstract : Invariant natural killer T (iNKT) cells are lipid‐specific T lymphocytes with important roles in antitumor immunity. Here, we demonstrated that intestinal and blood‐derived iNKT cells can eliminate human colon cancer (CRC) cells. We also showed that iNKT cells require the release of perforin and granzymes to kill CRC cells, using both innate and adaptive mechanisms to recognize them.