TY - JOUR
T1 - KIR-based inhibitory CARs overcome CAR-NK cell trogocytosis-mediated fratricide and tumor escape
AU - Li, Ye
AU - Basar, Rafet
AU - Wang, Guohui
AU - Liu, Enli
AU - Moyes, Judy S.
AU - Li, Li
AU - Kerbauy, Lucila N.
AU - Uprety, Nadima
AU - Fathi, Mohsen
AU - Rezvan, Ali
AU - Banerjee, Pinaki P.
AU - Muniz-Feliciano, Luis
AU - Laskowski, Tamara J.
AU - Ensley, Emily
AU - Daher, May
AU - Shanley, Mayra
AU - Mendt, Mayela
AU - Acharya, Sunil
AU - Liu, Bin
AU - Biederstädt, Alexander
AU - Rafei, Hind
AU - Guo, Xingliang
AU - Melo Garcia, Luciana
AU - Lin, Paul
AU - Ang, Sonny
AU - Marin, David
AU - Chen, Ken
AU - Bover, Laura
AU - Champlin, Richard E.
AU - Varadarajan, Navin
AU - Shpall, Elizabeth J.
AU - Rezvani, Katayoun
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/10
Y1 - 2022/10
N2 - Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their target, and (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells (NKTROG+) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a ‘don’t kill me’ signal to NK cells upon engagement with their TROG+ siblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.
AB - Trogocytosis is an active process that transfers surface material from targeted to effector cells. Using multiple in vivo tumor models and clinical data, we report that chimeric antigen receptor (CAR) activation in natural killer (NK) cells promoted transfer of the CAR cognate antigen from tumor to NK cells, resulting in (1) lower tumor antigen density, thus impairing the ability of CAR-NK cells to engage with their target, and (2) induced self-recognition and continuous CAR-mediated engagement, resulting in fratricide of trogocytic antigen-expressing NK cells (NKTROG+) and NK cell hyporesponsiveness. This phenomenon could be offset by a dual-CAR system incorporating both an activating CAR against the cognate tumor antigen and an NK self-recognizing inhibitory CAR that transferred a ‘don’t kill me’ signal to NK cells upon engagement with their TROG+ siblings. This system prevented trogocytic antigen-mediated fratricide, while sparing activating CAR signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.
UR - http://www.scopus.com/inward/record.url?scp=85139157265&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85139157265&partnerID=8YFLogxK
U2 - 10.1038/s41591-022-02003-x
DO - 10.1038/s41591-022-02003-x
M3 - Article
C2 - 36175679
AN - SCOPUS:85139157265
SN - 1078-8956
VL - 28
SP - 2133
EP - 2144
JO - Nature medicine
JF - Nature medicine
IS - 10
ER -