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

Nat Immunol. 2018 Jul;19(7):723-732. doi: 10.1038/s41590-018-0132-0. Epub 2018 Jun 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Neoplasms, Experimental / metabolism
  • Receptors, Immunologic / antagonists & inhibitors
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*


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