Gamma delta T cells in acute myeloid leukemia: biology and emerging therapeutic strategies

gamma delta T cells play an important role in disease control in acute myeloid leukemia (AML) and have become an emerging area of therapeutic interest. These cells represent a minor population of T lymphocytes with intrinsic abilities to recognize antigens in a major histocompatibility complex-independent manner and functionally straddle the innate and adaptive immunity interface. AML shows high expression of phosphoantigens and UL-16 binding proteins that activate the V delta 2 and V delta 1 subtypes of gamma delta T cells, respectively, leading to gamma delta T cell-mediated cytotoxicity. Insights from murine models and clinical data in humans show improved overall survival, leukemia-free survival, reduced risk of relapse, enhanced graft-versus-leukemia effect, and decreased graft-versus-host disease in patients with AML who have higher reconstitution of gamma delta T cells following allogeneic hematopoietic stem cell transplantation. Clinical trials leveraging gamma delta T cell biology have used unmodified and modified allogeneic cells as well as bispecific engagers and monoclonal antibodies. In this review, we discuss gamma delta T cells' biology, roles in cancer and AML, and mechanisms of immune escape and antileukemia effect; we also discuss recent clinical advances related to gamma delta T cells in the field of AML therapeutics.