A TIGIT-based chimeric co-stimulatory switch receptor improves T-cell anti-tumor function

Shiran Hoogi, Vasyl Eisenberg, Shimrit Mayer, Astar Shamul, Tilda Barliya, Cyrille J. Cohen

Research output: Contribution to journalArticlepeer-review

37 Scopus citations


BACKGROUND: Tumors can employ different mechanisms to evade immune surveillance and function. Overexpression of co-inhibitory ligands that bind to checkpoint molecules on the surface of T-cells can greatly impair the function of latter. TIGIT (T cell immunoreceptor with Ig and ITIM domains) is such a co-inhibitory receptor expressed by T and NK cells which, upon binding to its ligand (e.g., CD155), can diminish cytokine production and effector function. Additionally, the absence of positive co-stimulation at the tumor site can further dampen T-cell response. METHODS: As T-cell genetic engineering has become clinically-relevant in the recent years, we devised herein a strategy aimed at enhancing T-cell anti-tumor function by diverting T-cell coinhibitory signals into positive ones using a chimeric costimulatory switch receptor (CSR) composed of the TIGIT exodomain fused to the signaling domain of CD28. RESULTS: After selecting an optimized TIGIT-28 CSR, we co-transduced it along with tumor-specific TCR or CAR into human T-cells. TIGIT-28-equipped T-cells exhibited enhanced cytokine secretion and upregulation of activation markers upon co-culture with tumor cells. TIGIT-28 enhancing capability was also demonstrated in an original in vitro model of T-cell of hypofunction induction upon repetitive antigen exposure. Finally, we tested the function of this molecule in the context of a xenograft model of established human melanoma tumors and showed that TIGIT-28-engineered human T-cells demonstrated superior anti-tumor function. CONCLUSION: Overall, we propose that TIGIT-based CSR can substantially enhance T-cell function and thus contribute to the improvement of engineered T cell-based immunotherapy.

Original languageEnglish
Pages (from-to)243
Number of pages1
JournalJournal for ImmunoTherapy of Cancer
Issue number1
StatePublished - 9 Sep 2019


  • Chimeric receptors
  • Costimulation
  • T-cell engineering
  • Tumor immunotherapy


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