Early TRAIL-engagement elicits potent multimodal targeting of melanoma by CD34+ progenitor cell-derived NK cells
Amanda A. van Vliet,
Ella Peters,
Denise Vodegel,
Daniëlle Steenmans,
Monica Raimo,
Susan Gibbs,
Tanja D. de Gruijl,
Adil D. Duru,
Jan Spanholtz,
Anna-Maria Georgoudaki
Affiliations
Amanda A. van Vliet
Glycostem Therapeutics, Kloosterstraat 9, 5349 AB Oss, the Netherlands; Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands; Corresponding author
Ella Peters
Glycostem Therapeutics, Kloosterstraat 9, 5349 AB Oss, the Netherlands
Denise Vodegel
Glycostem Therapeutics, Kloosterstraat 9, 5349 AB Oss, the Netherlands
Daniëlle Steenmans
Glycostem Therapeutics, Kloosterstraat 9, 5349 AB Oss, the Netherlands
Monica Raimo
Glycostem Therapeutics, Kloosterstraat 9, 5349 AB Oss, the Netherlands
Susan Gibbs
Department of Molecular Cell Biology and Immunology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands
Tanja D. de Gruijl
Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, the Netherlands
Adil D. Duru
Glycostem Therapeutics, Kloosterstraat 9, 5349 AB Oss, the Netherlands
Jan Spanholtz
Glycostem Therapeutics, Kloosterstraat 9, 5349 AB Oss, the Netherlands
Anna-Maria Georgoudaki
Glycostem Therapeutics, Kloosterstraat 9, 5349 AB Oss, the Netherlands
Summary: Umbilical cord blood (UCB) CD34+ progenitor cell-derived natural killer (NK) cells exert efficient cytotoxicity against various melanoma cell lines. Of interest, the relative cytotoxic performance of individual UCB donors was consistent throughout the melanoma panel and correlated with IFNγ, TNF, perforin and granzyme B levels. Importantly, intrinsic perforin and Granzyme B load predicts NK cell cytotoxic capacity. Exploring the mode of action revealed involvement of the activating receptors NKG2D, DNAM-1, NKp30, NKp44, NKp46 and most importantly of TRAIL. Strikingly, combinatorial receptor blocking led to more pronounced inhibition of cytotoxicity (up to 95%) than individual receptor blocking, especially in combination with TRAIL-blocking, suggesting synergistic cytotoxic NK cell activity via engagement of multiple receptors which was also confirmed in a spheroid model. Importantly, lack of NK cell-related gene signature in metastatic melanomas correlates with poor survival highlighting the clinical significance of NK cell therapies as a promising treatment for high-risk melanoma patients.
