TIGIT as an emerging immune checkpoint

Abstract

T cell immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed on lymphocytes that was recently propelled under the spotlight as a major emerging target in cancer immunotherapy. TIGIT interacts with CD155 expressed on antigen-presenting cells or tumour cells to downregulate T cell and natural killer (NK) cell functions. TIGIT has emerged as a key inhibitor of anti-tumour responses that can hinder multiple steps of the cancer immunity cycle. Pre-clinical studies indicated that TIGIT blockade may protect against various solid and haematological cancers. Several monoclonal antibodies (mAbs) that block the inhibitory activity of human TIGIT have been developed. Clinical trials are ongoing, investigating TIGIT blockade as a monotherapy or in combination with anti-PD1/PD-L1 mAbs for the treatment of patients with advanced solid malignancies. In this review, we cover our current knowledge on TIGIT, from its discovery in 2009 to its current status as a clinical target.

CD155: A Multi-Functional Molecule in Tumor Progression

“…Of note, high expression of hCD96 on cells within the tumor microenvironment correlates with poor prognosis and resistance to chemotherapy [83,84], indicating hCD96 as a diagnostic marker. Finally, the expression of TIGIT correlates with functional NK and T cell impairment and poor prognosis in several types of cancers [85][86][87].…”

“…Regardless, both CD155 and its receptors represent promising targets for cancer immune therapy aimed to prevent exhaustion of tumor infiltrating lymphocytes [82]. In this context, six anti-TIGIT antibodies have entered clinical trials due to the promising results obtained in preclinical studies [85].…”

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

“…The PD-L1/2 expression on MM-cells can also be promoted through the stimulation of TLR ligands [40], interactions with MSCs [41] or signaling via APRIL [35]. While not much is known about the involvement of immune checkpoints Lag3 and TIM3 in MM progression, the T-cell immunoglobulin and ITIM domain (TIGIT), which is expressed on both T-and NK-cells [42], is perhaps another important immune checkpoint in MM. It has recently been shown that progression of MM was associated with high levels of TIGIT expression on CD8 + T-cells, which displayed impaired proliferative and cytokine responses upon non-specific and MM-antigen stimulation [43].…”

Proliferative and quiescent human gastric cancer stem-like cells are associated with differential chemoresistance and patient mortality

“…TIGIT is also known to be expressed on CD8 + T cells, and its expression often marks T cell dysfunction when NECTIN2 is bounded to the TIGIT receptor (Chauvin et al, 2015). Blocking the effect of TIGIT is being tested as a therapy for solid tumors (Harjunpää and Guillerey, 2020).…”