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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalJCI insight
Volume3
Issue number21
DOIs
StatePublished - Nov 2 2018

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Acute Myeloid Leukemia
T-Lymphocytes
Drug Therapy
Induction Chemotherapy
Immunity
Bone Marrow
Immunophenotyping
Organized Financing
Immunotherapy
Biomedical Research
Lymphoma
Cell Survival
Leukemia
Up-Regulation
Down-Regulation
Transplantation
Research Personnel
Gene Expression
Therapeutics
Research

Keywords

  • Cancer immunotherapy
  • Hematology
  • Immunology
  • Leukemias
  • T cells

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Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy. / Knaus, Hanna A.; Berglund, Sofia; Hackl, Hubert; Blackford, Amanda L.; Zeidner, Joshua F.; Montiel-Esparza, Raúl; Mukhopadhyay, Rupkatha; Vanura, Katrina; Blazar, Bruce R.; Karp, Judith; Luznik, Leo; Gojo, Ivana.

In: JCI insight, Vol. 3, No. 21, 02.11.2018.

Research output: Contribution to journalArticle

Knaus, HA, Berglund, S, Hackl, H, Blackford, AL, Zeidner, JF, Montiel-Esparza, R, Mukhopadhyay, R, Vanura, K, Blazar, BR, Karp, J, Luznik, L & Gojo, I 2018, 'Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy', JCI insight, vol. 3, no. 21. https://doi.org/10.1172/jci.insight.120974
Knaus, Hanna A. ; Berglund, Sofia ; Hackl, Hubert ; Blackford, Amanda L. ; Zeidner, Joshua F. ; Montiel-Esparza, Raúl ; Mukhopadhyay, Rupkatha ; Vanura, Katrina ; Blazar, Bruce R. ; Karp, Judith ; Luznik, Leo ; Gojo, Ivana. / Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy. In: JCI insight. 2018 ; Vol. 3, No. 21.
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AU - Berglund, Sofia

AU - Hackl, Hubert

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AU - Zeidner, Joshua F.

AU - Montiel-Esparza, Raúl

AU - Mukhopadhyay, Rupkatha

AU - Vanura, Katrina

AU - Blazar, Bruce R.

AU - Karp, Judith

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