Cancers, Vol. 12, Pages 1923: PVR and ICAM-1 on Blast Crisis CML Stem and Progenitor Cells with TKI Resistance Confer Susceptibility to NK Cells

Cancers, Vol. 12, Pages 1923: PVR and ICAM-1 on Blast Crisis CML Stem and Progenitor Cells with TKI Resistance Confer Susceptibility to NK Cells Cancers doi: 10.3390/cancers12071923 Authors: Nayoung Kim Mi-Yeon Kim Young-Uk Cho WenYong Chen Kyoo-Hyung Lee Hun Sik Kim The BCR-ABL1 fusion gene generating an oncogenic tyrosine kinase is a hallmark of chronic myeloid leukemia (CML), which can be successfully targeted by BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, treatment-free remission has been achieved in a minority of patients due to evolving TKI resistance and intolerance. Primary or acquired resistance to the approved TKIs and progression to blast crisis (BC), thus, remain a major clinical challenge that requires alternative therapeutic strategies. Here, we first demonstrate that donor natural killer (NK) cells prepared using a protocol adopted in clinical trials can efficiently eliminate CML-BC blasts, with TKI resistance regardless of BCR-ABL1 mutations, and preferentially target CD34+CD38− leukemic stem cells (LSC), a potential source of disease relapse. Mechanistically, the predominant expression of PVR, a ligand for the NK cell-activating DNAM-1 receptor, in concert with ICAM-1, a ligand for NK cell adhesion, confer this susceptibility to NK cells, despite the lack of ligands for NKG2D, a principal NK cell activating receptor, as an immune evasion mechanism. With these mechanistic insights, our findings provide a proof-of-concep...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Brief Report Source Type: research