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

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

Publication date: Sep 09, 2019

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.

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.

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.

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.

Hoogi, S., , Eisenberg, Mayer, S., Shamul, A., Barliya, T., and Cohen, C.J. A TIGIT-based chimeric co-stimulatory switch receptor improves T-cell anti-tumor function. 24075. 2019 J Immunother Cancer (7):1.

Concepts Keywords
Antigen Superior anti tumor
CD28 Culture tumor
Chimeric Melanoma tumors
CSR Immunotherapy
Cytokine Medicine
Genetic Engineering Medical specialties
Immune Surveillance Branches of biology
Immunotherapy Immune system
Ligand Cancer treatments
Ligands TIGIT
Melanoma T cells
Molecule Virotherapy
Receptor Immunotherapy
T Cell Genetic engineering
T Cells
Transduced
Tumor
Xenograft

Semantics

Type Source Name
pathway BSID Melanoma
disease DOID melanoma
disease MESH melanoma
gene UNIPROT ARR3
gene UNIPROT CXADR
gene UNIPROT CASR
gene UNIPROT NR1I3
gene UNIPROT SPG7
gene UNIPROT CD28
gene UNIPROT SCARA3
drug DRUGBANK S-Arsonocysteine
disease MESH tumor
gene UNIPROT TIGIT

Original Article

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