Molecular Pathways: Targeting CD96 and TIGIT for Cancer Immunotherapy.
The receptors CD96 and TIGIT are expressed on the surface of T and natural killer (NK) cells, and recent studies suggest both play important inhibitory roles in immune function. CD96 has been shown to modulate immune cell activity in mice, with Cd96-/-mice displaying hypersensitive NK-cell responses to immune challenge and significant tumor resistance. TIGIT overexpression has been shown to reduce NK-cell-mediated cytotoxicity. TIGIT is also upregulated on T cells during cancer and chronic viral infection, with expression associated with effector T-cell exhaustion and increased regulatory T-cell suppression. The counterbalance between the putative inhibitory CD96 and TIGIT receptors and the activating receptor, CD226, offers unique strategies for immuno-oncology drug development. Blocking CD96 or TIGIT with mAbs has been shown to improve tumor control in mice, in particular when used in combination with PD-1/PD-L1 blockade. These results have highlighted these pathways as promising new targets for immune modulation. This review will examine the rationale behind targeting CD96 and TIGIT, and discuss the potential approaches in translating these preclinical findings into novel clinical agents. Clin Cancer Res; 22(21); 5183-8. ©2016 AACR.
Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Stephen J
SJ
Blake
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
William C
WC
Dougall
Human Immunity Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|Institute of Infection and Immunity, Cardiff University, Cardiff, United Kingdom.|School of Medicine, The University of Queensland, Herston, Queensland, Australia.
John J
JJ
Miles
Cancer Immunoregulation and Immunotherapy, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.|School of Medicine, The University of Queensland, Herston, Queensland, Australia.
Michele W L
MW
Teng
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia. mark.smyth@qimrberghofer.edu.au.|School of Medicine, The University of Queensland, Herston, Queensland, Australia.
Mark J
MJ
Smyth
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D015703:Antigens, CD / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D011971:Receptors, Immunologic / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; C116131:CD96 antigen; D011971:Receptors, Immunologic