TIGIT expression is upregulated in T cells and causes T cell dysfunction independent of PD-1 and Tim-3 in adult B lineage acute lymphoblastic leukemia.

T cell immunoglobulin and ITIM domain (TIGIT) is a novel immune checkpoint receptor and plays critical roles in cancer immunity. Adult acute lymphoblastic leukemia (ALL) remains a treatment challenge despite years of research. In this study, we analyzed the status of TIGIT expression in circulating T cells from patients with adult ALL. Compared to the data in healthy controls, the expression of TIGIT in CD4CD25 T cells and CD8 T cells in adult ALL patients presented a small but significant upregulation. Stimulation via the CD3/CD28 route increased TIGIT mRNA expression at 24 h, which peaked at 48 h and was maintained at 72 h post-stimulation. The frequency of TIGIT cells, on the other hand, consistently increased over time. ALL protein lysate or Wilms' Tumor 1 peptide could significantly increase the expression of TIGIT in ALL, but not healthy control T cells. Compared to TIGIT cells, the TIGIT cells presented significantly higher PD-1 and Tim-3 expression directly ex vivo, and significantly lower IL-2, IFN-γ, and TNF-α after CD3/CD28 stimulation. The high inhibitory molecule and low cytokine expression signature was especially pronounced in ALL TIGIT CD4CD25 T cells and TIGIT CD8 T cells. Blocking TIGIT alone could minimally increase cytokine expression independent of PD-1 and Tim-3 blocking, whereas blocking TIGIT, PD-1, and Tim-3 altogether was significantly more effective. Together, these data demonstrated that TIGIT regulated T cell function in adult ALL patients, and may serve as a treatment target for ALL.