RT Journal Article
SR Electronic
T1 CIS checkpoint deletion enhances the fitness of cord blood derived natural killer cells transduced with a chimeric antigen receptor
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.03.29.014472
DO 10.1101/2020.03.29.014472
A1 May Daher
A1 Rafet Basar
A1 Elif Gokdemir
A1 Natalia Baran
A1 Nadima Uprety
A1 Ana Karen Nunez Cortes
A1 Mayela Mendt
A1 Lucila Nassif Kerbauy
A1 Pinaki P. Banerjee
A1 Mayra Hernandez Sanabria
A1 Nobuhiko Imahashi
A1 Li Li
A1 Francesca Lorraine Wei Inng Lim
A1 Mohsen Fathi
A1 Ali Rezvan
A1 Vakul Mohanty
A1 Yifei Shen
A1 Hila Shaim
A1 Junjun Lu
A1 Gonca Ozcan
A1 Emily Ensley
A1 Mecit Kaplan
A1 Vandana Nandivada
A1 Mustafa Bdaiwi
A1 Sunil Acharya
A1 Yuanxin Xi
A1 Xinhai Wan
A1 Duncan Mak
A1 Enli Liu
A1 Sonny Ang
A1 Luis Muniz-Feliciano
A1 Ye Li
A1 Jing Wang
A1 Shahram Kordasti
A1 Nedyalko Petrov
A1 Navin Varadarajan
A1 David Marin
A1 Lorenzo Brunetti
A1 Richard J. Skinner
A1 Shangrong Lyu
A1 Leiser Silva
A1 Rolf Turk
A1 Mollie S. Schubert
A1 Garrett R. Rettig
A1 Matthew S. McNeill
A1 Gavin Kurgan
A1 Mark A. Behlke
A1 Heng Li
A1 Natalie W. Fowlkes
A1 Ken Chen
A1 Marina Konopleva
A1 Richard Champlin
A1 Elizabeth J. Shpall
A1 Katayoun Rezvani
YR 2020
UL http://biorxiv.org/content/early/2020/03/30/2020.03.29.014472.abstract
AB Immune checkpoint therapy has produced remarkable improvements in the outcome for certain cancers. To broaden the clinical impact of checkpoint targeting, we devised a strategy that couples targeting of the cytokine-inducible SH2-containing (CIS) protein, a key negative regulator of interleukin (IL)-15 signaling, with chimeric antigen receptor (CAR) engineering of natural killer (NK) cells. This combined strategy boosted NK cell effector function through enhancing the Akt/mTORC1 axis and c-MYC signaling, resulting in increased aerobic glycolysis. When tested in a lymphoma mouse model, this combined approach improved NK cell anti-tumor activity more than either alteration alone, eradicating lymphoma xenografts without signs of any measurable toxicity. We conclude that combining CIS checkpoint deletion with CAR engineering promotes the metabolic fitness of NK cells in an otherwise suppressive tumor microenvironment. This approach, together with the prolonged survival afforded by CAR modification, represents a promising milestone in the development of the next generation of NK cells for cancer immunotherapy.