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Type: Journal article
Title: CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors
Author: Hughes, A.
Clarson, J.
Tang, C.
Vidovic, L.
White, D.
Hughes, T.
Yong, A.
Citation: Blood, 2017; 129(9):1166-1176
Publisher: American Society of Hematology
Issue Date: 2017
ISSN: 0006-4971
Statement of
Amy Hughes, Jade Clarson, Carine Tang, Ljiljana Vidovic, Deborah L. White, Timothy P. Hughes and Agnes S. M. Yong
Abstract: Immunological control may contribute to achievement of deep molecular response in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitor (TKI) therapy and may promote treatment-free remission (TFR). We investigated effector and suppressor immune responses in CML patients at diagnosis (n = 21), on TKI (imatinib, nilotinib, dasatinib) before achieving major molecular response (pre-MMR, BCR-ABL1 >0.1%, n = 8), MMR (BCR-ABL1 ≤0.1%, n = 20), molecular response4.5 (MR4.5, BCR-ABL1 ≤0.0032%, n = 16), and sustained TFR (BCR-ABL1 undetectable following cessation of TKI therapy, n = 13). Aberrant immune-inhibitory responses (myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and programmed death-1 (PD-1) inhibitory molecule expression on CD4+/CD8+ T cells were increased in CML patients at diagnosis. Consequent quantitative and functional defects of innate effector natural killer (NK) cells and cytotoxic T-lymphocyte responses to leukemia-associated antigens WT1, BMI-1, PR3, and PRAME were observed at diagnosis. Treg and PD-1+CD4+/CD8+ T cells persisted in pre-MMR CML patients on TKI. Patients in MMR and MR4.5 had a more mature, cytolytic CD57+CD62L- NK cell phenotype, consistent with restoration of NK cell activating and inhibitory receptor repertoire to normal healthy donor levels. Immune responses were retained in TFR patients off-therapy, suggesting the restored immune control observed in MMR and MR4.5 is not an entirely TKI-mediated effect. Maximal restoration of immune responses occurred only in MR4.5, as demonstrated by increased NK cell and effector T-cell cytolytic function, reduced T-cell PD-1 expression and reduced numbers of monocytic MDSCs.
Keywords: Killer Cells, Natural
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Antineoplastic Agents
Protein Kinase Inhibitors
Remission Induction
Flow Cytometry
Drug Resistance, Neoplasm
Aged, 80 and over
Middle Aged
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Enzyme-Linked Immunospot Assay
Programmed Cell Death 1 Receptor
Imatinib Mesylate
Myeloid-Derived Suppressor Cells
Rights: © 2017 by The American Society of Hematology
DOI: 10.1182/blood-2016-10-745992
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