Grant: Project Grant

Donor-derived hematopoietic stem cell transplantation (Allo-HSCT) is a potentially curative treatment for different types of blood cancers. However, recurrent diseases and treatment-associated toxicities caused by donor immune cells attacking the normal tissues of recipients, also known as graft-versus-host disease (GvHD), limit better clinical outcomes in allo-HSCT recipients. However, therapeutic approaches to treat or prevent relapse often increase the risks of GvHD and vice-versa. Hence, strategies that can address disease recurrence and GvHD are considered the ultimate goal for allo-HSCT recipients. Double-negative T (DNT) cell is a rare subset of immune cells. In laboratory settings, we have shown that DNTs can be easily obtained from healthy donors and are effective at killing leukemia without causing damage to healthy tissues. Donor-derived DNT cell therapy has been tested in a phase I clinical trial, where allo-HSCT patients with recurring diseases received the treatment. This study supported the feasibility, safety, and potential efficacy of DNT cell therapy in clinics. One unique feature of DNT cells is their ability to suppress the alloreactivity of T cells, an immunological activity that causes GvHD. In laboratory settings, we observed that DNT cells could suppress GvHD in animal models while improving the leukemia clearance rate. The central hypothesis of the study is that DNT cells contain functionally different subpopulations and selectively suppress GVHD in the absence of cancer cells while promoting cancer-targeting immune response in the presence of cancer cells. In addition to testing the hypothesis, the proposed work will dissect the underlying mechanism of how DNT cells suppress GvHD and promote cancer clearance using various in vitro and animal models. Gain- and loss-of-function experiments will be used to identify genes involved in the unique immunological function delivered by DNT cells.