Gene of the month: T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT)

Abstract

Immune modulators play a crucial role in carcinogenesis and cancer progression by impairing cancer cell-targeted immune responses. T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) regulates T-cell function and cancer cell recognition and was therefore identified as a promising target for cancer immunotherapy. TIGIT is expressed in T cells and natural killer (NK) cells and has three ligands: CD155, CD112 and CD113. CD155 binds TIGIT with the highest affinity and promotes direct and indirect downregulation of T-cell response. TIGIT signalling further inhibits NK function and secretion of proinflammatory cytokines. An association between TIGIT expression and poor survival was identified in multiple cancer entities. Blocking TIGIT with monoclonal antibodies, and a combination of TIGIT and programmed cell death protein 1 blockade in particular, prevented tumour progression, distant metastasis and tumour recurrence in in vivo models. Inhibition of TIGIT is currently evaluated in first clinical trials.

The current achievements of immune checkpoint inhibitor therapy in the treatment of cancer and the newly discovered immune checkpoints in recent years

“…Different T cell subsets, such as CD4+ T cells, CD8+ T cells, regulatory T cells (Treg), follicular T helper cells, and NK cells, show different levels of TIGIT expression. TIGIT acts as a negative regulator of cancer cell-targeted T cell responses and has been identified as a potential target for immune checkpoint inhibition in different malignancies [1] ." "The TIGIT effect is mediated by binding to CD155, the primary receptor for TIGIT, and directly inhibiting T cell responses.…”

“…These impaired DCs lead to an indirect decrease in T-cell responses. In TIGIT-regulated DCs, T cell proliferation is reduced by at least 50%, and T cell activation is inhibited [1] ." CD226 is a costimulatory receptor widely expressed by immune cells, including T cells, NK cells, and monocytes.…”

“…TIGIT-positive NK-cells exhibit diminished killing, reduced cytokine production and proliferation, and other features of exhaustion and dysfunction. TIGIT inhibits NK cell degranulation, cytokine production, and NK cell-mediated cytotoxicity against CD155-expressing tumor cells [1] ." "The basic principle of targeting TIGIT is to reverse the immune invasion of cancer cells and re-establish cytotoxicity against cancerous T cells and NK cells.…”

TIGIT in Lung Cancer: Potential Theranostic Implications

“…Moreover, TIGIT has been shown to regulate immune cell metabolism, suppressing glucose uptake and glycolysis in T cells through the inhibition of the Akt-mTOR pathway [15][16][17][18][19]. An association between TIGIT expression and poor survival was identified in multiple malignancies, although with controversial results [20].…”

“…Moreover, TIGIT has been shown to regulate immune cell metabolism, suppressing glucose uptake and glycolysis in T cells through the inhibition of the Akt-mTOR pathway [15][16][17][18][19]. An association between TIGIT expression and poor survival was identified in multiple malignancies, although with controversial results [20]. In this review, we highlight the current knowledge about TIGIT as a molecular target for lung cancer treatment across all current clinical trials employing anti-TIGIT mAbs; furthermore, we examine the role of TIGIT as a prognostic and predictive biomarker in human cancer, with a focus on immunohistochemistry and its possible prognostic, predictive, and overall theranostic applicaptions on lung cancer.…”