Open AccessProgrammed cell death 1‐expressing CD56‐negative natural killer (NK) cell expansion is a hallmark of chronic NK cell activation during dasatinib treatment
Author(s) -
Ishiyama Kenichi,
Kitawaki Toshio,
Otsuka Yasuyuki,
TakaoriKondo Akifumi,
Kadowaki Norimitsu
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.14692
Subject(s) - dasatinib , immunology , natural killer cell , interleukin 21 , interleukin 12 , medicine , lymphokine activated killer cell , cytotoxic t cell , immune system , cancer research , myeloid leukemia , biology , t cell , imatinib , biochemistry , in vitro
Dasatinib treatment markedly increases the number of large granular lymphocytes including natural killer (NK) cells in a proportion of Ph + leukemia patients, which associates with a better prognosis. In‐depth immune profiling of NK cells can predict therapeutic response in these patients. In the present study, we showed that CD56‐negative (CD56 neg ) NK cells increased exclusively in cytomegalovirus‐seropositive (CMV + ) patients treated with dasatinib. The increase longitudinally paralleled with progressive differentiation of CD56 dim NK cells during dasatinib therapy driven by CMV reactivation as shown by principal component analysis on 19 NK cell markers. The CD56 neg NK cells showed downregulation of NK‐activating receptors, upregulation of PD‐1, and lower cytotoxicity and cytokine production, indicating that these cells are anergic and dysfunctional as seen in chronic infections with HIV‐1 or hepatitis C virus. Moreover, cytolytic activity of CD56 dim and CD56 neg NK cells against leukemia cells was partially restored by nivolumab in proportion to the frequency of PD‐1 + NK cells. The proportion of patients who achieved deep molecular responses at 2 years was significantly higher in dasatinib‐treated patients with ≥3% CD56 neg NK cells than in those with fewer CD56 neg NK cells (54.5% vs 15.8%, P = .0419). These findings suggest that CD56 neg NK cells may be an exhausted population induced by chronic activation through CMV reactivation during dasatinib therapy. Expansion of CD56 neg NK cells is a hallmark of chronic NK cell activation in patients treated with dasatinib and may predict a better clinical outcome. Furthermore, PD‐1 blockade may enhance anti‐leukemia responses of such NK cells.