TIGIT/CD226 Axis Regulates Anti-Tumor Immunity

Abstract

Tumors escape immune surveillance by inducing various immunosuppressive pathways, including the activation of inhibitory receptors on tumor-infiltrating T cells. While monoclonal antibodies (mAbs) blocking programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have been approved for multiple cancer indications, only a subset of patients benefit from immune checkpoint blockade therapies, highlighting the need for additional approaches. Therefore, the identification of new target molecules acting in distinct or complementary pathways in monotherapy or combination therapy with PD-1/PD-L1 blockade is gaining immense interest. T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT) has received considerable attention in cancer immunotherapy. Recently, anti-TIGIT mAb (tiragolumab) has demonstrated promising clinical efficacy in non-small cell lung cancer treatment when combined with an anti-PD-L1 drug (Tecentriq), leading to phase III trial initiation. TIGIT is expressed mainly on T and natural killer cells; it functions as an inhibitory checkpoint receptor, thereby limiting adaptive and innate immunity. CD226 competes for binding with the same ligands with TIGIT but delivers a positive stimulatory signal to the immune cells. This review discusses the recent discoveries regarding the roles of TIGIT and CD226 in immune cell function and their potential application in cancer immunotherapy.

Preclinical and Exploratory Clinical Studies of Novel 68Ga-labeled ᴅ-Peptide Antagonist for PET Imaging of TIGIT Expression in Cancers

“…While TIGIT has been propelled under the spotlight as a next-generation target in cancer immunotherapy, anti-TIGIT therapy seems to be promising for a fraction of patients in clinical trials [14,15,23]. Therefore, patient strati cation is critical for this therapy, which could bene t from a whole-body, non-invasive and quantitative evaluation of TIGIT expression in cancer.…”

“…A growing number of studies have reported the blockade of TIGIT with antagonistic monoclonal antibodies (mAbs), which produce favorable therapeutic e cacy in preclinical and clinical trials [13]. To date, there are approximate ten human anti-TIGIT mAbs of IgG isotypes that have entered clinical trials for evaluating their e cacy and safety either as a monotherapy or in combination with anti-PD-1/PD-L1 mAbs or chemotherapeutics [14]. In a phase I trial, anti-TIGIT MK-7684 used as monotherapy and in combination with pembrolizumab in patients with advanced solid tumors was evaluated (NCT02964013) [13].…”

Perioperative Therapy for Non-Small Cell Lung Cancer with Immune Checkpoint Inhibitors

“…Monalizumab is an inhibitor of CD94/NK group 2 member A (NKG2A), an immune checkpoint molecule expressed on tumour-infiltrating cytotoxic T cells and natural killer cells [52]. Tiragolumab is a new immune checkpoint inhibitor blocking the interaction between T-cell immunoreceptors with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and CD155 (RVR) [53]. Canakinumab is a monoclonal antibody that neutralises IL-1β activity by blocking its interaction with the IL-1 receptor expressed on activated cytotoxic T cells and Tregs [54].…”

Perioperative Therapy for Non-Small Cell Lung Cancer with Immune Checkpoint Inhibitors

“…Monalizumab is an inhibitor of CD94/NK group 2 member A, an immune checkpoint molecule expressed on tumour-infiltrating cytotoxic T cells and natural killer cells [56]. Tiragolumab is a new immune checkpoint inhibitor blocking the interaction between Tcell immunoreceptors with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) and CD155 (RVR) [57]. Canakinumab is a monoclonal antibody that neutralises IL-1β activity by blocking its interaction with the IL-1 receptor expressed on activated cytotoxic T cells and Tregs [58].…”