Purpose: T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT) is a recently identified T-cell coinhibitory receptor. In this study, we aimed to determine the clinical impact of TIGIT in patients with acute myelogenous leukemia (AML) and dissect the role of TIGIT in the pathogenesis of leukemia progression.Experimental Design: TIGIT expression on T cells from peripheral blood collected from patients with AML was examined by flow cytometry. The correlation of TIGIT expression to clinical outcomes, including rate of complete remission and relapse post-allogeneic stem cell transplantation (alloSCT) in AML patients, was analyzed. Phenotypic and functional study (cytokine release, proliferation, killing, and apoptosis) of TIGIT-expressing T cells were performed. Using siRNA to silence TIGIT, we further elucidated the regulatory role of TIGIT in the T-cell immune response by dissecting the effect of TIGIT knockdown on cytokine release and apoptosis of T cells from AML patients.Results: TIGIT expression on CD8 þ T cells is elevated in AML patients and high-TIGIT correlates with primary refractory disease and leukemia relapse post-alloSCT. TIGIT þ CD8 þ T cells display phenotypic features of exhaustion and exhibit functional impairment manifested by low production of cytokines and high susceptibility to apoptosis. Importantly, their functional defects are reversed by TIGIT knockdown. Conclusions: TIGIT contributes to functional T-cell impairment and associates with poor clinical outcome in AML. Our study suggests that blockade of TIGIT to restore T-cell function and antitumor immunity may represent a novel effective leukemia therapeutic.

Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.