Molecular Pathways: Targeting CD96 and TIGIT for Cancer Immunotherapy

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.

Transcriptomic immunologic signature associated with favorable clinical outcome in basal-like breast tumors

“…TIGIT is a recently discovered immune receptor expressed in T cells and natural killers (NK) [9]. TIGIT has been described as overexpressed in CD8 expressing TILs in melanoma [16].…”

T cell exhaustion: from pathophysiological basics to tumor immunotherapy

“…The discovery of CD96 upregulation in T cells and NK cells within human tumors led to the the hypothesis that the inhibition of the CD155/CD96 could essentially influence the tumor elimination [162]. In particular, CD96 −/− mice show increased NK-cell activity in response to immune challenge and significant resistance to cancer [163, 164]. In addition, further studies could highlight the role of CD96 in acute myeloid leukaemia (AML) as well as in congenital disease like C syndrome or opitz trigonocephaly [165, 166].…”

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

“…This recognition should usually lead to killing of the DNAM-1L-bearing cell [36,37]. However, it is also possible that DNAM-1L can bind T cell immunoglobulin and ITIM domain (TIGIT) or CD96 inhibitory molecules on lymphocytes, leading to the impairment of immune response [38]. Moreover, NKG2DL and DNAM-1L are widely expressed in several carcinomas and leukemic disorders, suggesting that MSC, rather than tumor cells, can be an suitable alternative target in TME [36,37].…”