TY - JOUR
T1 - Early TRAIL-engagement elicits potent multimodal targeting of melanoma by CD34+ progenitor cell-derived NK cells
AU - van Vliet, Amanda A.
AU - Peters, Ella
AU - Vodegel, Denise
AU - Steenmans, Daniëlle
AU - Raimo, Monica
AU - Gibbs, Susan
AU - de Gruijl, Tanja D.
AU - Duru, Adil D.
AU - Spanholtz, Jan
AU - Georgoudaki, Anna-Maria
N1 - Funding Information: This research was funded by Eurostars , E∗11275 IMAGINe Publisher Copyright: © 2023 The Author(s)
PY - 2023/7/21
Y1 - 2023/7/21
N2 - 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.
AB - 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.
KW - Cancer
KW - Components of the immune system
KW - Therapy
UR - http://www.scopus.com/inward/record.url?scp=85163795784&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.isci.2023.107078
DO - https://doi.org/10.1016/j.isci.2023.107078
M3 - Article
C2 - 37426355
SN - 2589-0042
VL - 26
JO - iScience
JF - iScience
IS - 7
M1 - 107078
ER -