Studying TIGIT activity against tumors through the generation of knockout mice

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.

KEYWORDS:

• Fusion protein
• nectin
• PVR
• TIGIT
• TIGIT-KO mouse
• tumor

Acknowledgments

This work was supported by the following grants awarded to O.M.: the Israel Innovation Authority Kamin grant 62615, the German-Israeli Foundation for Scientific Research and Development grant 1412-414.13/2017, the ICRF professorship grant, the ISF Israel–China grant 2554/18, the MOST-DKFZ grant 3-14931, and the Ministry of Science and Technology grant 3-14764, by the Israel Science Foundation Moked grant 442-18.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Disclosure statement

The authors declare no conflicts of interest.

Additional information

Funding

The work was supported by the the Israel Innovation Authority Kamin grant [62615]; the German-Israeli Foundation for Scientific Research and Development grant [1412-414.13/2017]; the Israel Science Foundation Moked grant [442-18]; the MOST-DKFZ grant 3-14931 [3-14931]; the Ministry of Science and Technology grant [3-14764]; the ICRF professorship grant, the ISF Israel–China grant [2554/18].