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Evolution of T-Cell Fitness through AML Progression: Enhanced Bispecific T-Cell Engager-mediated Function of Bone Marrow T Cells at Remission Compared to Initial Diagnosis and Relapse [epigenome analysis]

ABSTRACT: To date, bispecific antibodies designed to engage T cells have failed to show sustained responses in relapsed/refractory acute myeloid leukemia (R/R AML). Bispecific antibodies, including bispecific T-cell-engager (BiTE) molecules, predominantly recruit T cells from the local immune microenvironment. Because they are mainly applied in the R/R setting, understanding the fitness of T cells from bone marrow in AML progression, is fundamental for advancing this platform. Here, by flow cytometry analysis of bone marrow-derived T cells, we identified distinct differentiation stages and expression of inhibitory receptors at initial diagnosis (ID) and relapse (RL). Longitudinal transcriptional analyses of paired ID and RL T cells showed a senescent phenotype at ID, whereas an exhausted and memory phenotype was dominant at RL. In line with these observations, T cells at RL exhibited higher BiTE-mediated cytotoxicity than ID T cells. Finally, we provide evidence that T cells, both from ID and RL, exhibit limited functional capacity following continuous BiTE exposure compared to T cells from complete remission. Our study provides insights into the different stages of T-cell phenotype and function during AML evolution. Correlative biomarker studies in patients treated with T-cell-based immunotherapies are needed, to better understand resistance mechanisms and to advance the platform.

ORGANISM(S): Homo sapiens

PROVIDER: GSE260999 | GEO | 2024/08/22

REPOSITORIES: GEO

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Evolution of T-Cell Fitness through AML Progression: Enhanced Bispecific T-Cell Engager-mediated Function of Bone Marrow T Cells at Remission Compared to Initial Diagnosis and Relapse [transcriptome analysis]

Project description:To date, bispecific antibodies designed to engage T cells have failed to show sustained responses in relapsed/refractory acute myeloid leukemia (R/R AML). Bispecific antibodies, including bispecific T-cell-engager (BiTE) molecules, predominantly recruit T cells from the local immune microenvironment. Because they are mainly applied in the R/R setting, understanding the fitness of T cells from bone marrow in AML progression, is fundamental for advancing this platform. Here, by flow cytometry analysis of bone marrow-derived T cells, we identified distinct differentiation stages and expression of inhibitory receptors at initial diagnosis (ID) and relapse (RL). Longitudinal transcriptional analyses of paired ID and RL T cells showed a senescent phenotype at ID, whereas an exhausted and memory phenotype was dominant at RL. In line with these observations, T cells at RL exhibited higher BiTE-mediated cytotoxicity than ID T cells. Finally, we provide evidence that T cells, both from ID and RL, exhibit limited functional capacity following continuous BiTE exposure compared to T cells from complete remission. Our study provides insights into the different stages of T-cell phenotype and function during AML evolution. Correlative biomarker studies in patients treated with T-cell-based immunotherapies are needed, to better understand resistance mechanisms and to advance the platform.

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