Targeting Glycolysis in Alloreactive T Cells to Prevent Acute Graft-Versus-Host Disease While Preserving Graft-Versus-Leukemia Effect
Ying Huang, Yujing Zou, Yiqun Jiao, Peijie Shi, Xiaoli Nie, Wei Huang, Chuanfeng Xiong, Michael Choi, Charles Huang, Andrew N. Macintyre, Amanda Nichols, Fang Li, Chuan‐Yuan Li, Nancie J. MacIver, Diana M. Cardona, Todd V. Brennan, Zhiguo Li, Nelson J. Chao, Jeffrey C. Rathmell, Benny J. Chen
Abstract
Alloreactive donor T cells undergo extensive metabolic reprogramming to become activated and induce graft-versus-host disease (GVHD) upon alloantigen encounter. It is generally thought that glycolysis, which promotes T cell growth and clonal expansion, is employed in this process. However, conflicting data have been reported regarding the requirement of glycolysis to induce T cell-mediated GVHD due to the lack of T cell-specific treatments using glycolysis inhibitors. Importantly, previous studies have not evaluated whether graft-versus-leukemia (GVL) activity is preserved in donor T cells deficient for glycolysis. As a critical component affecting the clinical outcome, it is necessary to assess the anti-tumor activity following treatment with metabolic modulators in preclinical models. In the present study, we utilized T cells selectively deficient for glucose transporter 1 (Glut1 T-KO ), to examine the role of glycolysis exclusively in alloreactive T cells without off-targeting effects from antigen presenting cells and other cell types that are dependent on glycolysis. We demonstrated that transfer of Glut1 T-KO T cells significantly improved acute GVHD outcomes through increased apoptotic rates, impaired expansion, and decreased proinflammatory cytokine production. In addition to impaired GVHD development, donor Glut1 T-KO T cells mediated sufficient GVL activity to protect recipients from tumor development. A clinically relevant approach using donor T cells treated with a small molecule inhibitor of glycolysis, 2-Deoxy-D-glucose ex vivo, further demonstrated protection from tumor development. These findings indicate that treatment with glycolysis inhibitors prior to transplantation selectively eliminates alloreactive T cells, but spares non-alloreactive T cells including those that protect against tumor growth. The present study has established a definitive role for glycolysis in acute GVHD and demonstrated that acute GVHD can be selectively prevented through targeting glycolysis.