Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity.

Abstract

Checkpoint blockade enhances effector T cell function and has elicited long-term remission in a subset of patients with a broad spectrum of cancers. TIGIT is a checkpoint receptor thought to be involved in mediating T cell exhaustion in tumors; however, the relevance of TIGIT to the dysfunction of natural killer (NK) cells remains poorly understood. Here we found that TIGIT, but not the other checkpoint molecules CTLA-4 and PD-1, was associated with NK cell exhaustion in tumor-bearing mice and patients with colon cancer. Blockade of TIGIT prevented NK cell exhaustion and promoted NK cell-dependent tumor immunity in several tumor-bearing mouse models. Furthermore, blockade of TIGIT resulted in potent tumor-specific T cell immunity in an NK cell-dependent manner, enhanced therapy with antibody to the PD-1 ligand PD-L1 and sustained memory immunity in tumor re-challenge models. This work demonstrates that TIGIT constitutes a previously unappreciated checkpoint in NK cells and that targeting TIGIT alone or in combination with other checkpoint receptors is a promising anti-cancer therapeutic strategy.

• Authors: Qing Zhang, Jiacheng Bi, Xiaodong Zheng, Yongyan Chen, Hua Wang, Wenyong Wu, Zhengguang Wang, Qiang Wu, Hui Peng, Haiming Wei, Rui Sun, Zhigang Tian
• Journal: Nature immunology (Nat Immunol) Vol. 19 Issue 7 Pg. 723-732 (07 2018) ISSN: 1529-2916 [Electronic] United States
• PMID: 29915296 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Immunologic
• T cell Ig and ITIM domain protein, mouse

Topics

• Adaptive Immunity
• Animals
• Cell Line
• Colonic Neoplasms (immunology)
• Humans
• Immunologic Memory
• Killer Cells, Natural (immunology)
• Lymphocytes, Tumor-Infiltrating (immunology)
• Melanoma, Experimental (immunology)
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Inbred NOD
• Mice, SCID
• Neoplasms, Experimental (immunology, metabolism)
• Receptors, Immunologic (antagonists & inhibitors, genetics, metabolism)