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

Area of Science:

• Immunology
• Cancer Biology
• Biotechnology

Background:

• Tumors evade immune surveillance by upregulating co-inhibitory ligands that impair T-cell function.
• TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a co-inhibitory receptor that reduces T-cell cytokine production and effector function upon ligand binding.
• Lack of co-stimulation at the tumor site further suppresses T-cell responses.

Purpose of the Study:

• To enhance T-cell anti-tumor function by converting inhibitory TIGIT signals into stimulatory signals.
• To develop a chimeric costimulatory switch receptor (CSR) by fusing the TIGIT exodomain with the CD28 signaling domain.

Main Methods:

• Constructed and optimized a TIGIT-28 CSR.
• Co-transduced human T-cells with the TIGIT-28 CSR along with tumor-specific T-cell receptor (TCR) or chimeric antigen receptor (CAR).
• Evaluated T-cell function in vitro using co-culture assays with tumor cells and a model of T-cell hypofunction, and in vivo using a human melanoma xenograft model.

Main Results:

• TIGIT-28-equipped T-cells showed enhanced cytokine secretion and activation marker expression when co-cultured with tumor cells.
• The TIGIT-28 CSR effectively reversed T-cell hypofunction induced by repetitive antigen exposure in vitro.
• TIGIT-28-engineered T-cells demonstrated superior anti-tumor activity in a human melanoma xenograft model.

Conclusions:

• TIGIT-based CSRs can significantly enhance T-cell function against tumors.
• This strategy holds promise for improving engineered T-cell-based immunotherapies.
• Converting inhibitory TIGIT signals into activating signals represents a novel approach to cancer immunotherapy.