Chimeric Antigen Receptor (CAR) therapy has revolutionized cancer immunotherapy, and recent advances have extended its application to natural killer (NK) cells. A critical component of optimizing CAR-NK cell efficacy lies in modulating NK cell regulatory receptors. TIGIT (T cell immunoreceptor with Ig and ITIM domains), an inhibitory receptor expressed on NK and T cells, binds with high affinity to CD155 (PVR), suppressing immune cell function. Here, we engineered a TIGIT-CAR construct that, in contrast to native TIGIT, delivers an activating rather than inhibitory signal upon CD155 engagement.
Using a pALD-based viral vector system, we introduced the human TIGIT-CAR construct into NK92-MI cells. Transduction efficiency was initially assessed via GFP reporter expression, and successful surface expression of TIGIT-CAR was confirmed by flow cytometry. TIGIT-expressing NK92-MI cells were sorted and utilized for functional assays.
Cytotoxicity was evaluated using an LDH release assay against tumor cell lines with differential CD155 expression. TIGIT-CAR NK cells demonstrated significantly enhanced cytolytic activity, degranulation (CD107a), and IFN-γ secretion against CD155-high A549 cells, but not against CD155-low K562 cells. These results indicate that TIGIT-CAR NK cells selectively recognize and kill CD155-expressing tumor cells.
This is the first report demonstrating the therapeutic potential of TIGIT-CAR NK cells against CD155-positive tumors. Future work will focus on in vivo efficacy and combinatorial strategies with immune checkpoint inhibitors. Given the frequent overexpression of CD155 in solid tumors such as ovarian and colorectal cancers, TIGIT-CAR NK therapy represents a promising strategy for targeted immunotherapy.