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Updated: Jul 28, 2025
Molecular and Immunologic Techniques in a Genetically Engineered Mouse Model of Gastrointestinal Stromal Tumor
Published on: May 2, 2022
Studying TIGIT activity against tumors through the generation of knockout mice
Ahmed Rishiq1, Reem Bsoul2, Ophir Pick1
1The Concern Foundation Laboratories at the Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Abstract:
The use of antibodies to block inhibitory receptors, primarily anti-PD1 and CTLA4 (known as checkpoint therapy) revolutionized cancer treatment. However, despite these successes, the majority of cancer patients do not respond to the checkpoint treatment, emphasizing the need for development of additional therapies, which are based on other inhibitory receptors. Human TIGIT is an inhibitory receptor expressed by Natural Killer (NK) and T cells and is mainly known to interact with PVR, Nectin-2, Nectin-3, and Nectin-4. Whether mouse TIGIT interacts with all of these ligands is still unclear. Additionally, the in vivo function of TIGIT against tumors is not completely understood. Here, we demonstrate that mouse TIGIT interacts with and is inhibited by mPVR only. Using CRISPR-Cas9 technology, we generated TIGIT-deficient mice and demonstrated that NK cell cytotoxicity and degranulation against two tumor types were lower in WT mice when compared to the TIGIT KO mice. Moreover, in vivo tumor progression was slower in TIGIT KO than in WT mice. Taken together, our data established that mTIGIT has only one ligand, PVR, and that in the absence of TIGIT tumors are killed better both in vitro and in vivo.
Insights
Mouse TIGIT, an inhibitory receptor, interacts only with PVR. Removing TIGIT enhances Natural Killer cell activity against tumors, slowing cancer progression in vivo and improving tumor cell killing.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Immune checkpoint therapy (anti-PD1, CTLA4) has transformed cancer treatment.
- Many patients do not respond to current immunotherapies, necessitating novel therapeutic targets.
- TIGIT is an inhibitory receptor on immune cells, but its function and ligands in mice are not fully understood.
Purpose of the Study:
- To investigate the ligands and in vivo function of mouse TIGIT.
- To determine if mouse TIGIT interacts with the same ligands as human TIGIT.
- To assess the impact of TIGIT deficiency on anti-tumor immunity.
Main Methods:
- CRISPR-Cas9 gene editing to generate TIGIT-deficient mice.
- Assessment of Natural Killer (NK) cell cytotoxicity and degranulation.
- In vivo tumor progression studies comparing wild-type (WT) and TIGIT knockout (KO) mice.
Main Results:
- Mouse TIGIT was found to interact exclusively with mouse PVR (mPVR).
- NK cell cytotoxicity and degranulation were reduced in WT mice compared to TIGIT KO mice.
- Tumor progression was significantly slower in TIGIT KO mice than in WT mice.
Conclusions:
- Mouse TIGIT has a single ligand, PVR.
- The absence of TIGIT enhances NK cell-mediated anti-tumor responses.
- Targeting TIGIT may represent a promising strategy for improving cancer immunotherapy.
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