PF268 DECIPHERING THE ABERRANT IMMUNE MICROENVIRONMENT IN ACUTE MYELOID LEUKEMIA DEVELOPMENT AND ITS ROLE IN CHEMOTHERAPY RESPONSE
Authors: L. Tang, H. Mei, Y. Hu, Z. Yin, L. Liu, H. Jiang, C. Li, M. Xu
Journal: HemaSphere (2019)

Background: Comprehensive illustration of phenotypic and functional signatures of abnormal immune microenvironment in acute myeloid leukemia (AML) is lacking. Aims: In this study, we dissected the aberrant immune microenvironment in AML development and its association with chemotherapy response, which may contribute to personalized therapy and provide new insight into novel immunotherapies to augment anti‐leukemia immunity. Methods: Phenotypic and functional analysis of various lymphocytes (eg. CD4+ T cells, CD8+ T cells, NK cells, TNK cells, γδ T cells and B cells) in peripheral blood (PB) and their prognostic implications were performed by multiparameter flow cytometry in 49 patients with AML (before or/and after induction chemotherapy) and 22 healthy controls (HCs). Results: The proportions of CD3+ T cells, NK cells, Th cells, Tc cells and γδ T cells in PB were higher in 25 newly‐diagnosed AML (ND‐AML) patients versus 22 HCs (each P &lt; 0.05). A significant increase in the proportion of CD4+ T (relative to CD3+ T cells), Tfh and Treg cells was also noted, but B cells and TNK cells were similar for ND‐AML and HCs (Fig.1A). As for memory subsets, we found a significantly reduced percentage of naïve subset (CD45RA+CCR7+, relative to CD4+ or CD8+ T cells) in AML at diagnosis. An aberrant unbalance among Th1, Th2, Th17 and Tfh1 cells was also demonstrated in ND‐AML patients. Additionally, the expression of chemokine receptor CCR4, CCR6 and CXCR3 was shown to be down‐regulated. To functionally characterize T cells and NK cells from newly diagnosed AML patients, we assessed several function‐related markers. Further analysis showed a significantly lower expression of CD28 and CD127 in CD4+ or CD8+ T cells, but a higher expression of senescence marker CD57 for ND‐AML versus HCs (Fig.1B). Meanwhile, the homing receptor CD38 and memory marker HLADR demonstrated higher expression in CD8+ T cells in ND‐AML versus HCs. NKG2D expression was found to be significantly lower in NK cells, Vδ1 cells and Vδ2 cells, as well as NKP30 expression in NK cells. The percentage of CD4+ T, CD8+ T, Vδ1 T and Vδ2 T cells expressing inhibitory receptor PD‐1 was significantly higher in AML compared with HCs. Following induction chemotherapy, the immune landscape of AML patients was altered as immune reconstitution occurred. The proportion of CD3+ T cells, CD8+ T naïve cells and Th2 cells increased after induction chemotherapy, with the elevated expression of NKG2D in NK and Vδ2 cells, CD28 and CD25 in CD4+ T cells and CD127 in CD8+ T cells. Several phenotypic and functional markers diverged between good responders (GR, n = 19) and refractory or relapsed (RR, n = 14) patients. Good response to induction chemotherapy significantly correlated with downregulation of PD‐1 and CD57 in CD8+ T cells, upregulation of NKG2D in NK cells and Vδ2 cells and increased proportion of CD8+ T naïve and Th17 cells (Fig.1C). Summary/Conclusion: Our findings suggest that exhaustion and senescence are the dominant aspects of aberrant immune states in AML at diagnosis. Chemotherapy response and relapse significantly correlate with suppressed immune microenvironment, indicating that immunological markers may be novel prognostic risk factor in acute myeloid leukemia. image