Association of TIM-3 checkpoint receptor expression on T cells with treatment-free remission in chronic myeloid leukemia.
Yazad Darius IraniChung Hoow KokJade ClarsonNaranie ShanmuganathanSusan BranfordDavid T YeungDavid Morrall RossTimothy P HughesAgnes Sm YongPublished in: Blood advances (2023)
Dysregulation of immune checkpoint receptors has been reported at diagnosis of chronic myeloid leukemia (CML), but their role in the maintenance of remission after tyrosine kinase inhibitor (TKI) cessation is unclear. We assessed PD-1, TIM-3, CTLA-4, LAG-3 and TIGIT expression on T-cell subsets, regulatory T cells (T-regs), and natural killer (NK) cells at the time of TKI cessation in 44 patients (22 who sustained treatment-free remission (TFR), 22 who experienced molecular relapse (MolR)). We confirmed our previous finding that absolute numbers of T-regs are increased in MolR patients compared to TFR. The immune checkpoint receptors PD-1, CTLA-4, LAG-3 and TIGIT on T or NK cells were not differentially expressed between the MolR and TFR groups. However, TIM-3 was consistently upregulated on bulk T-cells (CD3+), and T-cell subsets including, CD4+T-cells, CD8+T-cells, and T-regs, in patients who relapsed in comparison to those who maintained TFR after discontinuation. Furthermore, gene expression analysis from publicly available datasets showed increased TIM-3 expression on CML stem cells compared with normal hematopoietic stem cells. These findings suggest that among the targetable immune checkpoint molecules, TIM-3 blockade may potentially improve effector immune response in CML patients stopping TKI, whilst concomitantly targeting leukemic stem cells, and could be a promising therapeutic strategy for preventing relapse after cessation of TKI in CML patients.
Keyphrases
- chronic myeloid leukemia
- stem cells
- end stage renal disease
- regulatory t cells
- nk cells
- ejection fraction
- newly diagnosed
- immune response
- chronic kidney disease
- peritoneal dialysis
- prognostic factors
- gene expression
- tyrosine kinase
- acute myeloid leukemia
- advanced non small cell lung cancer
- acute lymphoblastic leukemia
- oxidative stress
- transcription factor
- cell cycle
- dna methylation
- copy number
- rna seq
- epidermal growth factor receptor
- hodgkin lymphoma