Programmed cell death 1-expressing CD56-negative natural killer (NK) cell expansion is a hallmark of chronic NK cell activation during dasatinib treatment.

ABSTRACT: 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.

SUBMITTER: Ishiyama KI 

PROVIDER: S-EPMC7893985 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature