Abstract
Chimeric antigen receptors (CAR) bearing PDZ binding motifs enhance tumor regression and survival.
Major Finding: Chimeric antigen receptors (CAR) bearing PDZ binding motifs enhance tumor regression and survival.
Concept: Intracellular scaffold-supported CAR synapses at the target–effector interface promote optimal immune signaling.
Impact: This work provides evidence for a strategy to improve the efficacy of CAR therapy in solid tumors.
Genetically engineered natural killer (NK) cells are designed to harness the antitumor killing capability of NK cells through exogenous expression of a cancer cell–targeted chimeric antigen receptor (CAR), which typically comprises an extracellular antigen-binding domain as well as intracellular activation and costimulation domains. Despite promising advances in this approach for the treatment of hematologic malignancies, CAR therapies remain ineffective in solid tumors, underscoring the need for strategies that enhance optimal CAR signaling. Because many CAR designs result in islands of disordered CAR–antigen complexes at the target–effector interface that may lead to inefficient immune cell signaling, Chockley and colleagues hypothesized that the formation of highly ordered CAR synapses may be required for optimal signaling and antitumor activity. CARs targeting tumor-associated antigens were modified to include the postsynaptic density-95, discs large and zona occuldens 1 (PDZ) binding motif (PDZbm) of an intracellular scaffolding protein known to be involved in immune synapse formation. Upon incubation of engineered NK cells with their cognate antigen, NK cells expressing a PDZbm-containing CAR construct (CAR.PDZ) induced higher levels of downstream signaling via ZAP70 and a more condensed synaptic area when compared with control CAR constructs. When NK cells were cocultured with cognate antigen–expressing cancer cells, CAR.PDZ-NK cells exhibited a stronger binding force, increased calcium flux, and faster lysosomal aggregation, with these phenotypes leading to improved NK-cell function, as indicated by enhanced secretion of perforin and IFNγ. In line with these results, CAR.PDZ-NK cells displayed increased cytolytic and migratory activity, further supporting the functional benefit of adding the PDZbm to support formation of the CAR synapse. Moreover, CAR.PDZ constructs demonstrated tumor regression and improved survival in multiple solid and brain tumor xenograft models when engineered into either NK cells or T cells, highlighting the broad applications of this strategy. Overall, this study reveals the potential clinical benefit of modulating CAR synapses to enhance antitumor therapies.
Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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