NKT-Like (CD3+CD56+) Cells in Chronic Myeloid Leukemia Patients Treated With Tyrosine Kinase Inhibitors

Abstract

Therapy with Tyrosine Kinase Inhibitors (TKI) aiming stable deep molecular response is the gold standard to treat Chronic Myeloid Leukemia (CML). NKT-like cells (CD3+CD56+) combine characteristics of T and NK cells. The physiopathological role of these cells remains unknown although the literature refers their association with inflammation, autoimmune diseases, and cancer. Since the information regarding the role of NKT-like cells in CML is rare, we aimed at the characterization of these cells in CML patients treated with TKIs. Peripheral blood NKT-like cells from 48 CML patients and 40 healthy donors were analyzed by multiparametric flow cytometry. Functional tests consisting of co-culture with leukemic target cells (K562 cell line) were used to measure degranulation and cytokine production. Our results revealed that NKT-like cells are decreased in treated CML patients, although they present increased expression of activation markers (CD69 and HLA-DR), increased degranulation (CD107a) and impaired IFN-γ production. Significantly alterations on the expression of tumor recognition (NCRs and NKp80), and immune regulation receptors (LAG-3, TIM-3, and CD137) by NKT-like cells were observed in CML patients. Second generation TKIs increased cell activation (CD69) and decreased expression of NKp44 and NKp80 by NKT-like cells from CML patients when compared to Imatinib. CML patients that achieved deep molecular response (MR4.5) presented downregulation of NKp44 and LAG-3. Further studies are needed to clarify the role of these cells as biomarkers of therapy response and also to evaluate their value for discrimination of better candidates for sustained treatment-free remission after TKI discontinuation.

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

“…In terms of immunosuppression in cancer, galectin-9 (Gal-9) is the most important TIM-3 ligand. In CML, increased expression of TIM-3 was detected on NKT cells [ 81 ]. Bruck et al identified increased expression of TIM-3, PD-1 and CTLA-4 on CD4+ and CD8+ T cells in the bone marrow of CML patients, compared with control samples [ 41 ].…”

“…It is suggested that tumor cells express MHC-II to bind with LAG-3 and inhibit TCR signaling on effector T cells. As LAG-3 is overexpressed on T cells in CML and AML patients [ 71 , 81 ], it could be yet another way to evade immune response by leukemic cells [ 98 ].…”

Exposure-related, global alterations in innate and adaptive immunity; a consideration for re-use of non-human primates in research

“…NKT cells are known to share receptors expressed by both T and NK cells ( Lanier, Spits & Phillips, 1992 ). Previous evidence also suggests expression of HLA-DR on NKT cells under certain disease conditions or changes in cytokine milieu ( Saikh, Kissner & Ulrich, 2002 ; Almeida et al, 2019 ), which may play an important role in inflammation and immune regulation ( Marrero, Ware & Kumar, 2015 ).…”

T-Cell Immune Imbalance in Rheumatoid Arthritis Is Associated with Alterations in NK Cells and NK-Like T Cells Expressing CD38

“…NK-like T cells are usually defined as CD3+ CD56+ cells and have also been referred to as CD56(+) T, NKT-like cells, and even NKT in published references. Studies on NK-like T cells in RA are scarce, and related knowledge is limited, controversial, and heterogeneous [58]. Accumulation of CD56 (+) T cells was detected in RA and may be involved in maladaptive immune responses, and these T cells have been suggested as potential targets for therapy [59].…”