Overexpression of TIGIT in NK and T Cells Contributes to Tumor Immune Escape in Myelodysplastic Syndromes

Abstract

Targeting immune checkpoints, such as PD-1, represents a promising approach for cancer immunotherapy, achieving long-term disease remission rates in numerous types of cancer. T cell immunoglobulin and ITIM domain (TIGIT) is a checkpoint receptor associated with the antitumor roles of NK and T cells. Notably, the blockade of TIGIT has been revealed as a potential promising approach in cancer immunotherapy. However, the therapeutic potential of blocking TIGIT in myelodysplastic syndrome (MDS) remains unclear and further research is required to reveal their role. Methods: Fresh peripheral blood (PB) and bone marrow (BM) were obtained from patients with MDS and healthy donors (HDs) at the Tianjin Medical University General Hospital between January 21 2018 and March 22 2019. The present study investigated the expression levels of TIGIT on NK and T cells using flow cytometry (FCM) and PCR. In addition, other checkpoint receptors, such as CD226 and PD-1, were also investigated. To determine the mechanisms of antitumor immunity, the functions of NK and T cells expressing TIGIT were determined. Results: TIGIT was found to be highly expressed on NK and T cells of the PB, where it was involved in disease progression and the immune escape of MDS. The high expression levels of TIGIT were associated with decreased NK and T cell function, and significantly lower secretions of activation factors, such as CD107a, IFN-γ and TNF-α. Notably, blocking TIGIT enhanced the antitumor effects of NK and T cells. Conclusion: The results of the present study suggested that targeting TIGIT alone or in combination with PD-1 may be a promising anticancer therapeutic strategy in MDS.

A Systematic Review and Meta-Analysis on the Significance of TIGIT in Solid Cancers: Dual TIGIT/PD-1 Blockade to Overcome Immune-Resistance in Solid Cancers

“…Stanietsky et al have shown that TIGIT can inhibit NK cells cytotoxicity, and its blockade can upregulate interferon-γ (IFN-γ) [ 32 ]. Meng et al have reported that TIGIT + NK cells express fewer IFN-γ and tumor necrosis factor-α (TNF-α) than TIGIT-NK cells, and the high expression of TIGIT is associated with decreased function of NK cells and immune evasion of tumoral cells [ 33 ]. Moreover, TIGIT has been implicated in impairing the anti-tumoral immune responses of CD8 + T-cells.…”

Detection of Immune Checkpoint Receptors – A Current Challenge in Clinical Flow Cytometry

“…Reports about the TIGIT expression on NK-cells in patients with malignant diseases are indecisive. Increased expression of TIGIT on NK-cells in the peripheral blood has been reported in patients with myelodysplastic syndrome ( 230 ), high risk non-muscle invasive bladder cancer ( 231 ) and gastrointestinal cancer (gastric and colon cancer) ( 171 ). Patients with colon cancer show higher TIGIT expression on NK-cells in intratumoral regions than in peritumoral regions ( 232 ).…”

Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes

“…T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a novel coinhibitory receptor expressed by T and NK cells that binds to CD155, leading to impaired T or NK cell anti-tumorigenic functions ( 98 ). TIGIT is an emerging target in cancer immunotherapy where its activation in T cells by its ligand CD155 or CD112 expressed by cancer cells inhibits T cell responses ( 99 ).…”