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

Abstract

γδ 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 Vδ2 and Vδ1 subtypes of γδ T cells, respectively, leading to γδ 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 γδ T cells following allogeneic hematopoietic stem cell transplantation. Clinical trials leveraging γδ T cell biology have used unmodified and modified allogeneic cells as well as bispecific engagers and monoclonal antibodies. In this review, we discuss γδ T cells’ biology, roles in cancer and AML, and mechanisms of immune escape and antileukemia effect; we also discuss recent clinical advances related to γδ T cells in the field of AML therapeutics.

Granulocyte Colony Stimulating Factor-Mobilized Peripheral Blood Mononuclear Cells: An Alternative Cellular Source for Chimeric Antigen Receptor Therapy

“…In addition to this, the mechanism of action is based on the release of cytotoxic granules such as perforin and granzyme; expressing death receptor ligands such as FasL, which induces apoptosis when it binds to its receptor on the target cell; or binding to antibody-coated cells through the CD16 receptor, triggering antibody-dependent cellular antibodies and releasing cytotoxic granules. In γ/δ T cells [ 17 ], the mechanism of action is very similar, including the release of perforin and granzymes, FasL ligand, and CD16 expression. However, these cells can recognize non-classical MHC-I molecules such as MIC-A as well as CD1, which is present in lipid antigens.…”

GNL3L exhibits pro-tumor activities via NF-κB pathway as a poor prognostic factor in acute myeloid leukemia

“…The prognosis of AML varies by subtype and decreases with age with an overall 5-year survival rate of less than 30% 2 . Although intensive cytarabine-based chemotherapy 3 and allogeneic hematopoietic stem cell transplantation (alloHSCT) 4 , as well as other emerging therapies such as chimeric antigen receptor T cell (CAR-T) 5 , have greatly improved survival in AML, a significant proportion of patients do not benefit from them due to intolerance and resistance. The development in identification of cytogenetic abnormalities, mutations and dysregulations of oncogenes and onco-suppressor genes 6 has provided new insights into the pathogenesis of AML.…”