title: CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors.
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-ABL1undetectable 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 MR4.5had 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 MR4.5is 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.
authors.affiliation: Department of Haematology, SA Pathology, Adelaide, SA, Australia.|Cancer Theme, South Australia Health and Medical Research Institute, Adelaide, SA, Australia; and.|School of Medicine, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: Amy
authors.initials: A
authors.lastname: Hughes
authors.affiliation: Department of Haematology, SA Pathology, Adelaide, SA, Australia.|Cancer Theme, South Australia Health and Medical Research Institute, Adelaide, SA, Australia; and.
authors.forename: Jade
authors.initials: J
authors.lastname: Clarson
authors.affiliation: Department of Haematology, SA Pathology, Adelaide, SA, Australia.
authors.forename: Carine
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Haematology, SA Pathology, Adelaide, SA, Australia.
authors.forename: Ljiljana
authors.initials: L
authors.lastname: Vidovic
authors.affiliation: Cancer Theme, South Australia Health and Medical Research Institute, Adelaide, SA, Australia; and.|School of Medicine, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: Deborah L
authors.initials: DL
authors.lastname: White
authors.affiliation: Department of Haematology, SA Pathology, Adelaide, SA, Australia.|Cancer Theme, South Australia Health and Medical Research Institute, Adelaide, SA, Australia; and.|School of Medicine, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.affiliation: Department of Haematology, SA Pathology, Adelaide, SA, Australia.|Cancer Theme, South Australia Health and Medical Research Institute, Adelaide, SA, Australia; and.|School of Medicine, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: Agnes S M
authors.initials: AS
authors.lastname: Yong
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D000069439:Dasatinib / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm / Q000276:immunology*; D058501:Enzyme-Linked Immunospot Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D000072737:Myeloid-Derived Suppressor Cells / Q000187:drug effects / Q000276:immunology; D061026:Programmed Cell Death 1 Receptor / Q000096:biosynthesis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use; D012074:Remission Induction
chemical_list: D000970:Antineoplastic Agents; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib; D000069439:Dasatinib