Natural killer (NK) cells play a critical role in tumor immunosurveillance. Multiple activating and inhibitory receptors (IR) regulate NK-cell–mediated tumor control. The IR T-cell immunoglobulin and ITIM domain (TIGIT) and its counter-receptor CD226 exert opposite effects on NK-cell–mediated tumor reactivity.

We evaluated the frequency, phenotype, and functions of NK cells freshly isolated from healthy donors and patients with melanoma with multiparameter flow cytometry. We assessed TIGIT and CD226 cell surface expression and internalization upon binding to CD155. We evaluated the role of IL15 and TIGIT blockade in increasing NK-cell–mediated cytotoxicity in vitro and in two mouse models.

NK cells are present at low frequencies in metastatic melanoma, are dysfunctional, and downregulate both TIGIT and CD226 expression. As compared with TIGIT⁻ NK cells, TIGIT⁺ NK cells exhibit higher cytotoxic capacity and maturation, but paradoxically lower cytotoxicity against CD155⁺ MHC class I–deficient melanoma cells. Membrane bound CD155 triggers CD226 internalization and degradation, resulting in decreased NK-cell–mediated tumor reactivity. IL15 increases TIGIT and CD226 gene expression by tumor-infiltrating NK cells (TiNKs) and, together with TIGIT blockade, increases NK-cell–mediated melanoma cytotoxicity in vitro and decreases tumor metastasis in two mouse melanoma models. Specific deletion of TIGIT on transferred NK cells enhances the antimetastatic activity of IL15, while CD226 blockade decreases the effects of IL15 and TIGIT blockade.

Our findings support the development of novel combinatorial immunotherapy with IL15 and TIGIT blockade to promote NK-cell–mediated destruction of MHC class I–deficient melanoma, which are refractory to CD8⁺ T-cell–mediated immunity.

See related commentary by Pietra et al., p. 5274