Dasatinib in CML: Activating Natural Killer Cells
Posted: Friday, March 8, 2019
If chronic myeloid leukemia (CML) were the theme of a superhero movie, the lead caped character in the current treatment landscape might well be the natural killer (NK) cell. As Ming-Chih Chang, MD, of MacKay Memorial Hospital, Taipei, Taiwan, and colleagues noted in their Frontiers in Immunology article, “NK cell activation and expansion [are] associated with optimal treatment responses…. Intriguingly, CML patients who had an expansion of mature NK cells after tyrosine kinase inhibitor (TKI) treatments could successfully discontinue the treatments, as suggested in recent studies, emphasizing the important role of immunosurveillance by mature NK populations.”
Although all TKIs inhibit BCR-ABL formation and “have drastically improved overall [CML] patient survival,” dasatinib, distinct from imatinib and nilotinib, contributes to particularly accelerated molecular responses. To better understand this phenomenon, the authors examined the effects and mechanisms of TKIs on the activating and inhibitory NK receptors in NK cells isolated from patients with CML in chronic phase.
Dr. Chang and co-investigators discovered that dasatinib features animmunomodulatory mechanism that specifically suppresses the inhibitory NK receptor NKG2A. Along with direct inhibition of ABL kinase, “this additional function of dasatinib…explains why successful anti-CML treatments by dasatinib often accompany peripheral NK lymphocytosis,” revealed the team. In other words, “enhanced cytotoxic NK cell expression in dasatinib-treated CML patients could be due to the unique downregulation of NKG2A by dasatinib.”
However, the authors acknowledged some reports suggest that dasatinib is immunosuppressive on NK cellsin vitroand in mouse models. So, they concluded, future work that quantifies the “intricate balance” between activating and inhibitory NK signaling “may help clarify these contradicting issues.”
Disclosure: The study authors reported no conflicts of interest.