Association of TIM-3 checkpoint receptor expression on T cells with treatment-free remission in chronic myeloid leukemia

Abstract

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.

Multiomic single-cell analysis identifies von Willebrand factor and TIM3-expressingBCR-ABL1+CML stem cells

“…We also identified significant cell surface overexpression of TIM3 when comparing CML LSC with normal HSC, which is in line with a previous report showing upregulated TIM3 gene expression ( HAVCR2 ) in CML LSC based on mining of publicly available RNA-seq datasets 29 . In addition, TIM3 is reportedly overexpressed and critical for self-renewal of LSC in acute myeloid leukemia (AML) 23,24,30 .…”

Single-cell analysis of immune recognition in chronic myeloid leukemia patients following tyrosine kinase inhibitor discontinuation

“…Interestingly, blocking of TIM3 in the co-culture assays also led to increased IFN-γ secretion although no clear effect on target cell killing was seen. A recent study identified elevated HAVCR2 /TIM3 in CD8 + T cells from patients with relapse following TKI withdrawal [ 51 ] as we noted in our PR1-specific CD8 + T cells. As such, immune-checkpoint inhibitors targeting TIGIT and TIM3 are interesting molecular targets to induce more potent NK cell engagement against CML cells, but further studies are needed with larger cohort of primary CML cells.…”

Immune modulation in chronic myeloid leukaemia patients treated with nilotinib and interferon‐alpha

“…Immune suppressors including T-regs and monocytic MDSCs have been shown to play a critical role in successful TFR. 9,50,51 Our data demonstrate that addition of IFN to nilotinib does not alter the downward trajectory of immune suppressors from diagnosis to DMR.…”

“…Here we show MDSCs rapidly decreased following nilotinib therapy, likely due to targeting of BCR::ABL1 ‐positive MDSCs by TKI, 49 and were not affected by the addition of IFN, remaining at low‐level long term. Immune suppressors including T‐regs and monocytic MDSCs have been shown to play a critical role in successful TFR 9,50,51 . Our data demonstrate that addition of IFN to nilotinib does not alter the downward trajectory of immune suppressors from diagnosis to DMR.…”