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Updated: Sep 13, 2025
Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
Published on: March 7, 2025
TIGIT Affects CAR NK-cell Effector Function in the Solid Tumor Microenvironment by Modulating Immune Synapse Strength
Ishwar Navin1, Matthew Dysthe2, Prashant S Menon3
1Department of Immunology and Microbiology, Baylor College of Medicine, Houston, Texas.
Abstract:
Therapies using NK cells that express chimeric antigen receptors (CAR-NK) have been successfully employed against hematologic malignancies. However, solid tumors resist CAR-NKs partly by enriching tumor microenvironments with ligands for NK cell inhibitory receptors. Although the NK inhibitory receptor T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) has been implicated in impaired antitumor activity of endogenous NK cells, the consequences of TIGIT expression on engineered CAR-NKs have not been explored. To address this gap, we compared TIGIT-expressing and TIGIT-deleted human CAR-NKs targeting the GD2 solid tumor antigen in tumor immune microenvironment co-cultures and in vivo tumor immune microenvironment xenografts designed to mimic the immunosuppressive environment of solid tumors. TIGIT-deleted GD2.CAR-NKs exhibited antitumor activity, expanded, and persisted within TIGIT ligand-enriched solid tumor environments, whereas TIGIT-expressing CAR-NKs did not. Mechanistic experiments revealed that the improved tumor control resulting from TIGIT loss on CAR-NKs was not dependent on DNAM-1 activation or enhanced cytotoxic potential but rather on downregulation of cell adhesion molecules, weakened cell avidity, and reduced synapse contact duration that, in concert, improved serial killing and allowed more efficient tumor destruction. Our study highlights a noncanonical role for TIGIT in modulating CAR-NK activity that may guide strategies to overcome inhibitory NK receptors like TIGIT and improve the efficacy of CAR-NKs against solid tumors.
Insights
Deleting the TIGIT receptor from chimeric antigen receptor (CAR)-NK cells enhances their ability to fight solid tumors. This modification improves CAR-NK cell persistence and efficacy in immunosuppressive tumor microenvironments.
Area of Science:
- Immunology
- Cancer Biology
- Cell Therapy
Background:
- Chimeric antigen receptor (CAR)-NK cell therapies show promise against blood cancers.
- Solid tumors create immunosuppressive microenvironments that limit CAR-NK cell effectiveness.
- The role of TIGIT, an NK cell inhibitory receptor, in CAR-NK cell function against solid tumors is unknown.
Purpose of the Study:
- To investigate the impact of TIGIT expression on the anti-tumor activity of GD2-targeted CAR-NK cells in solid tumor models.
- To compare the efficacy of TIGIT-deleted versus TIGIT-expressing CAR-NK cells in immunosuppressive environments.
Main Methods:
- Co-culture systems and in vivo xenografts mimicking solid tumor microenvironments (TiME) were used.
- TIGIT-expressing and TIGIT-deleted human GD2.CAR-NK cells were compared for anti-tumor activity, expansion, and persistence.
- Mechanistic studies explored the role of TIGIT in cell adhesion, synapse formation, and serial killing.
Main Results:
- TIGIT-deleted GD2.CAR-NK cells demonstrated significant anti-tumor activity, expansion, and persistence in TIGIT ligand-rich tumor environments.
- TIGIT-expressing CAR-NK cells showed impaired anti-tumor function under similar conditions.
- TIGIT deletion improved tumor control by downregulating cell adhesion molecules, reducing avidity and synapse duration, enhancing serial killing, and increasing tumor destruction efficiency.
Conclusions:
- TIGIT plays a novel, non-canonical role in modulating CAR-NK cell activity against solid tumors.
- Deleting TIGIT from CAR-NK cells can overcome inhibitory receptor-mediated resistance in solid tumors.
- Targeting TIGIT offers a potential strategy to enhance CAR-NK cell therapy efficacy for solid tumors.
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