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 (CD56neg) NK cells increased exclusively in cytomegalovirus‐seropositive (CMV+) patients treated with dasatinib. The increase longitudinally paralleled with progressive differentiation of CD56dim NK cells during dasatinib therapy driven by CMV reactivation as shown by principal component analysis on 19 NK cell markers. The CD56neg 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 CD56dim and CD56neg 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% CD56neg NK cells than in those with fewer CD56neg NK cells (54.5% vs 15.8%, P = .0419). These findings suggest that CD56neg NK cells may be an exhausted population induced by chronic activation through CMV reactivation during dasatinib therapy. Expansion of CD56neg 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.

Immune Dysfunctions of CD56neg NK Cells Are Associated With HIV-1 Disease Progression

“…NK cell function relies on the expression patterns of activating and inhibitory receptors. Phenotypic characterization of CD56 neg NK cells revealed a loss of certain activating receptors, such as the natural cytotoxicity receptors NKp30 and NKp46, as well as decreased expression of NKG2A (14,44). Given that NK cell activation relies on an integration of signals from activating and inhibitory receptors, the alteration of NK cell receptor expression may indirectly influence the CD56 neg NK cell response in HIV-1infected patients.…”

NK Cell Subpopulations and Receptor Expression in Recovering SARS-CoV-2 Infection

“…CD56 neg NK cells were observed to be phenotypically more closely related to CD56 dim NK cells than CD56 bright NK cells. Thus, results obtained by principal component analysis (PCA) [ 23 ] and by studies focusing on epigenetic modifications, [ 24 , 25 ] showed that CD56 neg cells display a transcriptional feature more similar to that of CD56 dim than to that of CD56 bright NK cells.…”

Expanded NK cells from umbilical cord blood and adult peripheral blood combined with daratumumab are effective against tumor cells from multiple myeloma patients

“…12,13 Some reports indicate that PD-L1 expression in tumor cells results in functional impairment of PD-1 + NK cells. [14][15][16] While certain reports show that NK cell function can be partially restored using blocking mAbs, 15,16 others show a more acute impairment that requires cytokines such as IL-2 and IL-15 for functional restoration. 14 Regarding NK cells, additional molecules act as checkpoint inhibitors, such as the inhibitory NK cell receptor NKG2A, which inhibits NK cell activity when ligated by HLA-E, expressed on the surface of tumor cells.…”