Bona fide cytotoxic iNKT cells with superior antitumour responses identified in mice and humans

Adoptive cell therapies (ACT) using unmodified or engineered invariant Natural Killer T (iNKT) cells are in clinical trials for cancer treatment. While promising, outcomes are still suboptimal, possibly due to iNKT cell heterogeneity. This study identified unique iNKT cell populations with strong cytotoxic activity in mice and humans. In mice, iNKT1c cells showed potent CD1d-dependent and -independent antitumor functions, with responses influenced by NK receptors. IL-15 enhances their cytolytic activity, while retinoic acid is essential for their generation. In humans, terminally differentiated CD57+ iNKT cells showed marked NK-receptor expression and most effectively killed C1R tumor cells in vitro. These cells appeared activated/exhausted within tumors of non-small cell lung cancer patients. Additionally, a central memory-like CD62L+ CD4- iNKT subset efficiently expanded and generated cytotoxic CD57+ iNKT cells in vitro, making them an appealing candidate for ACT. This study paves the way for the design of more effective iNKT cell-based immunotherapies.