Marin, Krasnick, and Becker-Hapak et al. showed that in patients with advanced melanoma (AM), mostly immature NK cells expressing low levels of perforin and granzyme B infiltrated uninvolved lymph nodes and metastases, and blood NK cells expressed low levels of NK activating receptors. IL-12/15/18 induction of memory-like (ML) NK cells from the blood of healthy donors and patients with AM boosted NK cell lysis of melanoma cells. Blockade of NKG2D and NKp46 activating receptors reduced melanoma cell lysis by autologous ML NK cells. In immunodeficient mice, a human melanoma cell line was better controlled by transferred human ML than control NK cells.
Contributed by Paula Hochman
ABSTRACT
PURPOSE: Treatment of advanced melanoma (AM) is a clinical challenge. 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 anti-tumor 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 pre-clinical activity of ML NK against solid tumors remains largely undefined. EXPERIMENTAL DESIGN: Phenotypic and functional alterations of blood and AM infiltrating NK cells were evaluated using mass cytometry. ML NK from healthy donors (HD) and AM patients were evaluated for their ability to produce IFN-g and kill melanoma targets in vitro and in vivo using a xenograft model. RESULTS: NK cells in AM exhibited a decreased cytotoxic potential compared to blood NK cells. ML NK cells differentiated from HD and AM patients displayed enhanced ability of IFN-g 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. Further, in xenograft NSG mouse models, human ML NK cells demonstrated superior control of melanoma, compared to conventional NK cells. CONCLUSIONS: Blood NK cells from healthy donors or AM patients 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.
Author Info: (1) Department of Medicine, Washington University in St. Louis School of Medicine. (2) Surgery, Washington University in St. Louis School of Medicine. (3) Medicine, Washington Univ
Author Info: (1) Department of Medicine, Washington University in St. Louis School of Medicine. (2) Surgery, Washington University in St. Louis School of Medicine. (3) Medicine, Washington University in St. Louis School of Medicine. (4) Section of Surgical Oncology, Dept. of Surgery, Washington University in St. Louis School of Medicine. (5) Surgery, Washington University in St. Louis School of Medicine. (6) Medicine, Washington University in St. Louis School of Medicine. (7) Section of Surgical Oncology, Dept. of Surgery, Washington University in St. Louis School of Medicine. (8) Medicine, Washington University in St. Louis School of Medicine. (9) Medicine, Washington University in St. Louis School of Medicine. (10) Medicine, Washington University in St. Louis School of Medicine. (11) Medicine, Washington University in St. Louis School of Medicine. (12) Dept. of Medicine, Division of Oncology, Washington University in St. Louis School of Medicine. (13) Section of Surgical Oncology, Dept. of Surgery, Washington University in St. Louis School of Medicine. (14) Dept. of Medicine, Division of Oncology, Washington University in St. Louis School of Medicine. (15) Dept. of Medicine, Division of Oncology, Washington University in St. Louis School of Medicine. (16) Dept. of Medicine, Division of Oncology, Washington University in St. Louis School of Medicine. (17) Dept. of Medicine, Division of Oncology, Washington University in St. Louis School of Medicine. (18) Dept of Medicine, Division of Oncology, Washington University in St. Louis School of Medicine. (19) Surgery, Washington University in St. Louis School of Medicine. (20) Dept of Medicine, Division of Oncology, Washington University in St. Louis School of Medicine tfehnige@wustl.edu.
