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CML patients with deep molecular responses to TKI have restored immune effectors, decreased PD-1 and immune suppressors

Amy Hughes, Jade Clarson, Carine Tang, Ljiljana Vidovic, Deborah L. White, Timothy P. Hughes and Agnes S.M. Yong

Key points

  • Increased immune suppressors and PD-1 abrogates effector responses in CML patients at diagnosis.

  • Enhanced net effector immune responses, decreased PD-1 and immune suppressors may promote sustained deep molecular response in CML.

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) prior to 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 (MDSC), regulatory T cells (Treg) 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- natural killer (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-MDSC.

  • Submitted October 17, 2016.
  • Accepted December 17, 2016.