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Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy
Hanna A. Knaus, … , Leo Luznik, Ivana Gojo
Hanna A. Knaus, … , Leo Luznik, Ivana Gojo
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e120974. https://doi.org/10.1172/jci.insight.120974.
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Clinical Medicine Hematology Immunology

Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy

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Abstract

BACKGROUND. Our understanding of phenotypic and functional signatures of CD8+ T cell dysfunction in acute myeloid leukemia (AML) is limited. Deciphering these deranged T cell functional states and how they are impacted by induction chemotherapy is essential for incorporation of novel immune-based strategies to restore and maintain antileukemia immunity. METHODS. We utilized high-dimensional immunophenotyping, gene expression, and functional studies to characterize peripheral blood and bone marrow CD8+ T cells in 72 AML patients at diagnosis and after induction chemotherapy. RESULTS. Our data suggest that multiple aspects of deranged T cell function are operative in AML at diagnosis, with exhaustion and senescence being the dominant processes. Following treatment, the phenotypic and transcriptional profile of CD8+ T cells diverged between responders and nonresponders. Response to therapy correlated with upregulation of costimulatory, and downregulation of apoptotic and inhibitory, T cell signaling pathways, indicative of restoration of T cell function. In functional studies, AML blasts directly altered CD8+ T cell viability, expansion, co-signaling and senescence marker expression. This CD8+ T cell dysfunction was in part reversible upon PD-1 blockade or OX40 costimulation in vitro. CONCLUSION. Our findings highlight the uniqueness of AML in sculpting CD8+ T cell responses and the plasticity of their signatures upon chemotherapy response, providing a compelling rationale for integration of novel immunotherapies to augment antileukemia immunity. FUNDING. This work was supported by the Leukemia & Lymphoma Society grant no. 6449-13; NIH grants UM1-CA186691 and R01-HL110907-01; the American Society for Blood and Marrow Transplantation New Investigator Award/Gabrielle’s Angel Foundation; the Vienna Fund for Innovative Cancer Research; and by fellowships from the Wenner-Gren Foundation and the Swedish Society for Medical Research.

Authors

Hanna A. Knaus, Sofia Berglund, Hubert Hackl, Amanda L. Blackford, Joshua F. Zeidner, Raúl Montiel-Esparza, Rupkatha Mukhopadhyay, Katrina Vanura, Bruce R. Blazar, Judith E. Karp, Leo Luznik, Ivana Gojo

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Figure 1

CD8+ T cells from AML patients display phenotypical features of exhaustion and senescence, but are able to secrete cytokines.

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CD8+ T cells from AML patients display phenotypical features of exhausti...
Pretreatment PB T cells from newly diagnosed AML patients (n = 20) and healthy controls (HCs) (n = 18) were analyzed by multiparameter flow cytometry. P values were calculated using Mann–Whitney U test (A–E). (A) CD8+ T cell subsets according to CD45RA and CCR7 (left), and CD45RA and CD27 (right). (B and C) Expression of (B) stimulatory receptors, and (C) the senescence marker CD57, and IRs (2B4, PD-1) on CD8+ T cells. (D) Boolean gating analysis of the coexpression of PD-1, CD57, and 2B4 on PB CD8+ T cells. Pie slices represent the number of coexpressed markers (0–3) analyzed with SPICE software. (E) Expression of effector molecules and cytokines on CD8+ T cells.

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