Molecular pathways: targeting CD96 and TIGIT for cancer immunotherapy
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Abstract 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.
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CD96 inhibits NK cell activity in murine cancer models.
“These include the TIM-3, LAG-3, TIGIT, and B- And T-Lymphocyte-Associated Protein (BTLA) receptors associated with T cell exhaustion as well as VISTA, a receptor found on tumor-infiltrating myeloid cells, whose inhibition promoted anti-tumor immune responses in murine models, and CD96, which has been shown to inhibit NK cell activity in murine cancer models (115–117).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [116]
VISTA inhibition promoted anti-tumor immune responses in murine models.
“These include the TIM-3, LAG-3, TIGIT, and B- And T-Lymphocyte-Associated Protein (BTLA) receptors associated with T cell exhaustion as well as VISTA, a receptor found on tumor-infiltrating myeloid cells, whose inhibition promoted anti-tumor immune responses in murine models, and CD96, which has been shown to inhibit NK cell activity in murine cancer models (115–117).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [116]
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Research works printed but not linked: 1
- Joller N, Lozano E, Burkett PR, Patel B, Xiao S, Zhu C, et al. Treg cells expressing the coinhibitory molecule TIGIT selectively inhibit proinflammatory Th1 and Th17 cell responses. Immunity. 2014;40:569-81.
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Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations
Seidel, J. A., Otsuka, A., & Kabashima, K. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00086 · Cited by 1,360 · see citing works
- Authors
- Blake, S. J., Dougall, W. C., Miles, J. J., Teng, M. W. L., & Smyth, M. J.
- Affiliations
- QIMR Berghofer Medical Research Institute (AU)
- The University of Queensland (AU)
- Corresponding author
- Smyth, Mark J.
- Venue
- Clinical Cancer Research
- Published
- 2016-10-31
- Volume
- 22
- Issue
- 21
- Pages
- 5183-5188
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2520704033
- Cited by
- 223
- References
- 52
- Citations by year
- 2026: 9 · 2025: 20 · 2024: 17 · 2023: 20 · 2022: 26 · 2021: 28 · 2020: 38 · 2019: 26 · 2018: 26 · 2017: 11 · 2016: 2
- FWCI
- 2.09
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- ResearchOnline - JCU (James Cook University) (submittedVersion)
- Funders
- National Health and Medical Research Council (1088960, 1093566)
- Cancer Council Queensland (1083776)
- Cancer Research Institute (1078671)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Cell Function and Interaction
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- CD96, TIGIT, CD226, cancer immunotherapy, natural killer cells, T cells, immune checkpoint inhibitors, T cell exhaustion, regulatory T cells, PD-1/PD-L1 blockade, monoclonal antibodies, tumor immunology
- MeSH terms
- Animals, Antibodies, Monoclonal, Humans, Immunotherapy, Killer Cells, Natural, Neoplasms, Receptors, Immunologic, Antigens, CD, T-Lymphocytes, Regulatory
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