Grant: Travel Awards - Institute Community Support

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents treatment with curative potential for individuals with hematological malignancies. Nevertheless, the prognosis for allo-HSCT recipients experiencing disease relapse or graft-versus-host disease (GvHD) is notably bleak, and the treatment of one condition invariably heightens susceptibility to the other. Consequently, the development of therapeutic modalities capable of concurrently addressing relapse and GvHD assumes paramount significance within the context of allo-HSCT. Our focus centers on CD3+CD4-CD8- double-negative T cells (DNTs), an unconventional subset of mature T cells exhibiting pronounced anti-leukemia efficacy. A recent phase I clinical trial substantiates the feasibility, safety, and potential anti-leukemic efficacy of allogeneic DNT therapy in patients experiencing relapsed acute myeloid leukemia (AML) post-allo-HSCT. Our investigation involves elucidating the impact of DNTs on the anti-leukemic and GvHD-inducing activities of conventional T (Tconv) cells. Intriguingly, DNTs exhibit a synergistic interaction with Tconv cells, enhancing anti-leukemic activity both in vitro and xenograft models. Mechanistically, DNTs release soluble factors that activate and potentiate the anti-leukemic capacities of Tconv cells. Conversely, DNTs demonstrate a suppressive effect on the GvHD-inducing activities of Tconv cells, operating in a CD18-dependent manner through cytotoxicity against proliferative Tconv cells. The seemingly dichotomous immunological activities of DNTs are contingent upon the presence or absence of AML cells. In summary, our findings support the potential adjunctive role of DNTs in the context of allo-HSCT. Their ability to concurrently mitigate disease relapse and GvHD positions them as a promising therapeutic strategy to enhance the efficacy and safety profile of allo-HSCT in the treatment of hematological malignancies.