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• W2966528196 abstract "Abstract Immunotherapy targeting T cell inhibitory mechanisms, such as the PD-1 pathway to unleash the anti-tumor immune response is a promising strategy for cancer treatment. Several studies including ours have demonstrated an involvement of PD-1 and other inhibitory T cell receptors in AML progression. Eomesodermin (Eomes) and T-bet are both T box transcription factors that are crucial in regulating T cell function. Recent studies showed that Eomes and T-bet differentially regulate PD-1 expression and T cell exhaustion in chronic viral infection. Here we examine the effect of these two transcription factors in the pathogenesis of AML using blood samples collected from a large cohort (n=59) of patients with AML. We report that Eomes+T-betintCD8 T cells are increased in AML. Importantly they are functionally impaired and associate with poor clinical outcome. We first performed flow cytometry analyses to examine the intracellular expression of Eomes and T-bet in CD8 T cells of blood samples collected from AML patients at initial diagnosis. Based on the level of Eomes vs. T-bet, three subpopulations were defined among activated CD8 T cells: Eomes- T-bethi, Eomes+ T-bethi, and Eomes+T-betint. We observed a significant increase in the percentage of Eomes+T-betint CD8 T cells from AML patients (n=59) compared to that of healthy donors (n=15) (21.97±1.85% vs. 13.47±2.92%, P=0.0367). In addition, we assessed blood samples from 11 AML patients at initial diagnosis compared to that from the same patients when they are in complete remission (CR). We found that the frequency of Eomes+T-betint CD8 T cells was significantly lower in CR. This finding suggests an association of Eomes+T-betint CD8 T cells with AML progression. We next evaluated the clinical correlation of different Eomes and T-bet expression pattern in AML. Based on the frequency of Eomes+T-betint CD8 T cells, we defined high- (Eomes+T-betint ≥21.72 %) vs. low-(Eomes+T-betint We further dissected the phenotype and functional status of each T cell subpopulation. The distribution of naive, central memory, effector memory and terminal differentiated profile was similar among Eomes+T-betint CD8 T cells compared with that of Eomes+ T-bethi and Eomes- T-bethi cells. However, intracellular production of IFN-γ upon in vitro anti-CD3/CD28 stimulation was significantly lower in Eomes+T-betint CD8 T cells compared with that in the other two subpopulations (n=47, P To study the effect of Eomes and T-bet in leukemia antigen-specific T cells, we performed a functional assay to detect CD8 T cell response against a WT-1 (a known leukemia-associated antigen) epitope. Purified CD8 T cells derived from HLA-A*0201+ AML patients were co-cultured in vitro with T2 cells (antigen presenting cells) pulsed with HLA-A*0201-binding WT1126-134 or SV40 LT281-289 (as negative control) peptide. Intracellular production of IFN-γ was detected in 1.2% of CD8 T cells after 6 days of stimulation with WT-1 peptide, while essentially 0 CD8 cells responded to control peptide. Importantly Eomes+T-betint leukemia-specific CD8 T cells (gated on IFN-γ+) were less functional as they produced less TNF-α compared with that of the other two subpopulations. Taken together, our study demonstrates a significant association of Eomes+T-betint T cells to immune dysfunction and poor clinical outcome in AML patients. This novel finding provides a great potential to define the prognostic biomarker and therapeutic target for this devastating blood cancer. Disclosures No relevant conflicts of interest to declare." @default.
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• W2966528196 date "2017-12-07" @default.
• W2966528196 modified "2023-09-30" @default.
• W2966528196 title "Eomes+ T-betint CD8 T Cells Are Functionally Impaired and Associate with Primary Refractory Disease in Patients with Acute Myeloid Leukemia (AML)" @default.
• W2966528196 doi "https://doi.org/10.1182/blood.v130.suppl_1.108.108" @default.
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