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 E. 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

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy'. Together they form a unique fingerprint.

  • Cite this

    Knaus, H. A., Berglund, S., Hackl, H., Blackford, A. L., Zeidner, J. F., Montiel-Esparza, R., Mukhopadhyay, R., Vanura, K., Blazar, B. R., Karp, J. E., Luznik, L., & Gojo, I. (2018). Signatures of CD8+ T cell dysfunction in AML patients and their reversibility with response to chemotherapy. JCI Insight, 3(21). https://doi.org/10.1172/jci.insight.120974