Mechanisms of TIGIT-driven immune suppression in cancer

Abstract

TIGIT is a co-inhibitory molecule that limits T cell proliferation and activation. TIGIT expression has been recently shown to identify a subset of regulatory T cells (Treg) that specifically suppresses Th1 and Th17 responses; however its role in tumor immunity has not been examined. Here, we determined whether TIGIT has a role in the suppression of anti-tumor immune responses. We found that TIGIT is highly up-regulated on Treg and CD8+ tumorinfiltrating lymphocytes (TILs) in multiple pre-clinical cancer models. Importantly, TIGIT expression is strongly associated with expression of other co-inhibitory molecules; PD-1, Tim-3 and Lag-3 and with production of IL-10 in Treg and CD8+ TILs. Moreover, TIGIT+ CD8+ TILs display an exhausted phenotype determined by decreased production of IL-2 and TNF-α. To understand whether TIGIT acts as a checkpoint in anti-tumor response, we monitored growth of implanted B16 melanoma in TIGIT -/mice and found that absence of TIGIT significantly delayed tumor growth. As TIGIT is expressed on both T cells (Treg and CD8+) and NK cells in cancer, we addressed the role of TIGIT in these subsets in driving immune suppression. Our data indicate that TIGIT may play a dominant role in Treg in that deficiency of TIGIT in Treg alone results in better control of tumor growth and a heightened proliferative response in the draining lymph nodes and spleens of tumor-bearing mice. Finally, we show that a TIGIT blocking antibody can be used therapeutically to decrease tumor growth and that blockade of TIGIT synergizes with Tim-3 blockade to maximally decrease tumor growth. Our study is the first report showing that TIGIT acts as an immune checkpoint in cancer. Importantly, our data indicate that TIGIT and Tim-3 synergize to suppress anti-tumor responses and targeting these two molecules could provide a therapeutic effect on tumor growth.

Combination cancer immunotherapy and new immunomodulatory targets

“…4). Tigit knockout mice show delayed tumour growth in a syngeneic melanoma model, an effect that can be traced in part to expression of TIGIT on T Reg cells 139 . However, much of the activity ascribed to TIGIT involves the interaction of TIGIT on T cells and perhaps natural killer cells with CD155 expressed on immature or resting dendritic cells, which blocks maturation signals normally delivered by CD226.…”

Novel Immunomodulatory Pathways in the Immunoglobulin Superfamily

“…Regardless, and in support of the Genentech antibody experiments , TIGIT knockout mice showed reduced tumor growth in a syngeneic melanoma model (Sema Kurtulus et al 2014 ). Further, an anti-TIGIT antibody was synergistic with an anti-TIM-3 antibody in controlling tumor growth (Sema Kurtulus et al 2014 ). The early data accumulating around TIGIT and interacting proteins suggest that targeting TIGIT may be especially benefi cial in tumor environments where both T cells and NK cells are demonstrated to be present and DC maturation may be stimulated, as in tumors in which tertiary lymphoid organization is observed.…”

“…This raises the question of whether lower doses, when properly controlled for IgG isotype, were ineffective. Regardless, and in support of the Genentech antibody experiments , TIGIT knockout mice showed reduced tumor growth in a syngeneic melanoma model (Sema Kurtulus et al 2014 ). Further, an anti-TIGIT antibody was synergistic with an anti-TIM-3 antibody in controlling tumor growth (Sema Kurtulus et al 2014 ).…”

The New Era of Cancer Immunotherapy

“…The contribution of the TIGIT pathway to tumor immune evasion has been consistently verified in different preclinical settings. Despite the lack of spontaneous autoimmunity in TIGIT knockout mice, tumor growth is significantly reduced in these mice in a T and NK cell-dependent manner ( Johnston et al, 2014;Kurtulus et al, 2014). Both human and murine tumor-infiltrating T cells express high levels of TIGIT, and TIGIT inhibition, by either genetic ablation or blocking mAbs, increases T-cell activation and proliferation in response to both polyclonal and antigen-specific stimulation ( Johnston et al, 2014;Joller et al, 2011;Lozano et al, 2012).…”

“…To date, antagonist anti-TIGIT mAbs have not demonstrated dramatic antitumor activity as single agents. However, coblockade of TIGIT and either PD-L1 ( Johnston et al, 2014) or TIM3 have proven synergistic against different solid tumors in mouse models (Kurtulus et al, 2014). It is therefore likely that TIGIT blockade will ultimately find application in combination with antagonist anti-PD1/PDL-1 or anti-Tim3 mAbs in the clinic.…”