Author ORCID Identifier
0000-0001-7727-0875
Date of Graduation
5-2023
Document Type
Dissertation (PhD)
Program Affiliation
Immunology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Katayoun Rezvani
Committee Member
Michael A. Curran
Committee Member
Ken Chen
Committee Member
Vahid Afshar-Kharghan
Committee Member
Yair Reisner
Committee Member
Navin Varadarajan
Committee Member
Michael R. Green
Abstract
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 the 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 targets, (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 (aCAR) against the cognate tumor antigen and an NK self-recognizing inhibitory CAR (iCAR) 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 aCAR-signaling against the tumor antigen, and resulted in enhanced CAR-NK cell activity.
Keywords
chimeric antigen receptor, NK cell, cellular engineering, trogocytosis, anti-tumor therapy, immunotherapy