Memory-like differentiation enhances NK cell responses to melanoma

Nancy D. Marin, Bradley A. Krasnick, Michelle Becker-Hapak, Leah Conant, Simon P. Goedegebuure, Melissa M. Berrien-Elliott, Keenan J. Robbins, Jennifer A. Foltz, Mark Foster, Pamela Wong, Celia C. Cubitt, Jennifer Tran, Christopher B. Wetzel, Miriam Jacobs, Alice Y. Zhou, David Russler-Germain, Lynne Marsala, Timothy Schappe, Ryan C. Fields, Todd A. Fehniger

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


Purpose: Treatment of advancedmelanoma is a clinical challenge. Natural killer (NK) cells are a promising cellular therapy for T cell- refractory cancers, but are frequently deficient or dysfunctional in patients with melanoma. Thus, new strategies are needed to enhance NK-cell antitumor responses. Cytokine-induced memory-like (ML) differentiation overcomes many barriers in the NK-cell therapeutics field, resulting in potent cytotoxicity and enhanced cytokine production against blood cancer targets. However, the preclinical activity of ML NK against solid tumors remains largely undefined. Experimental Design: Phenotypic and functional alterations of blood and advanced melanoma infiltrating NK cells were evaluated using mass cytometry. ML NK cells from healthy donors (HD) and patients with advanced melanoma were evaluated for their ability to produce IFNγ and kill melanoma targets in vitro and in vivo using a xenograft model. Results: NK cells in advanced melanoma exhibited a decreased cytotoxic potential compared with blood NK cells. ML NK cells differentiated from HD and patients with advanced melanoma displayed enhanced IFNγ production and cytotoxicity against melanoma targets. This included ML differentiation enhancing melanoma patients' NK-cell responses against autologous targets. The ML NK-cell response against melanoma was partially dependent on the NKG2D- and NKp46-activating receptors. Furthermore, in xenograft NSG mouse models, human ML NK cells demonstrated superior control of melanoma, compared with conventional NK cells. Conclusions: BloodNKcells from allogeneicHDor patients with advanced melanoma can be differentiated into ML NK cells for use as a novel immunotherapeutic treatment for advanced melanoma, which warrants testing in early-phase clinical trials.

Original languageEnglish
Pages (from-to)4859-4869
Number of pages11
JournalClinical Cancer Research
Issue number17
StatePublished - Sep 1 2021


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