Decitabine Conditioning Improves Natural Killer Cell Maturation and Limits CD8+ T Cell Terminal Differentiation Post-Allogeneic Stem Cell Transplantation in Acute Myeloid Leukemia Patients

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• Characterizing the NK and T cell immune landscape in AML patients post-alloSCT • Decitabine (DAC) conditioning improves NK cell maturation post-alloSCT • DAC conditioning limits CD8 + T cell terminal differentiation post-alloSCT • Donor NK/T cells from DAC conditioned patients remained functional post-alloSCT • DAC conditioning may potentially improve GVT immunity in AML patients Allogeneic stem cell transplantation (alloSCT) can be curative for acute myeloid leukemia (AML) patients due to graft-versus-tumor immune responses. However, relapse post-alloSCT remains a major clinical challenge, underscoring the necessity for adjuvant treatments that both reduce tumor load before alloSCT and strengthen natural killer (NK) and T cell immunity posttransplant. The hypomethylating agent decitabine (DAC) holds promise as it is well-tolerated and has direct anti-proliferative and pro-apoptotic effects on leukemic cells. In addition, DAC modulates tumor immunogenicity and exhibits immunomodulatory properties. Yet, integral insight into the impact of DAC addition to the pre-alloSCT conditioning on the immunophenotype and function of NK and T cells post-alloSCT is lacking. Here, we investigated the immunomodulatory effects of adding DAC to the pre-alloSCT conditioning on the NK and T cell landscape and function in AML patients post-transplantation. This retrospective cohort study included AML patients who received alloSCT with (n=30) or without (n=22) DAC as part of the condition regimen. Peripheral blood samples were collected three and six months post-alloSCT. High dimensional flow cytometry was used to assess the phenotypic profiles, whereas proliferation, cytokine production and cytotoxicity assays were performed to study their function. Irrespective of the conditioning regimen, checkpoint molecules on NK cells, including PD-1, TIM-3, LIGHT and OX40 were low post-alloSCT. Notably, DAC conditioning significantly increased the abundance of mature NK cell clusters co-expressing KIRah, KIRb, CD69, CD57 and DNAM-1. Interestingly, NK cells from DAC conditioned patients retained their cytotoxic and cytokine production capacity, with mature NK cells demonstrating significantly enhanced responsiveness to K562 stimulation compared to immature NK cells. Within the CD4 + T cells, DAC conditioning reduced the frequencies of T H1 /T H17 cells and a proportion of T H17 cells. Interestingly, DAC treatment led to a diminished abundance of CD8 + T cell clusters co-expressing immune checkpoint molecules, including PD-1, TIGIT, KLRG1, TIM-3 and CD57, implying a less terminally differentiated phenotype. Functionally, CD4 + and CD8 + T cells from DAC conditioned patients demonstrated robust proliferation in response to anti-CD3 stimulation and exhibited polyfunctionality, producing IFN-γ, TNF-α and IL-2. Notably, the higher abundance of CD8⁺ T cells co-expressing inhibitory checkpoint molecules in non-DAC-conditioned patients was inversely associated with IL-2 production upon polyclonal stimulation. Overall, addition of DAC to the conditioning regimen was associated with favorable immunomodulatory effects on NK and T cells post-alloSCT in AML patients. These findings suggest that DAC may enhance donor NK and T cell-mediated graft-versus-tumor responses supporting its further clinical evaluation as an adjuvant prior to alloSCT.

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