Chromatin mapping and single-cell immune profiling define the temporal dynamics of ibrutinib response in CLL

Abstract

The Bruton tyrosine kinase (BTK) inhibitor ibrutinib provides effective treatment for patients with chronic lymphocytic leukemia (CLL), despite extensive heterogeneity in this disease. To define the underlining regulatory dynamics, we analyze high-resolution time courses of ibrutinib treatment in patients with CLL, combining immune-phenotyping, single-cell transcriptome profiling, and chromatin mapping. We identify a consistent regulatory program starting with a sharp decrease of NF-κB binding in CLL cells, which is followed by reduced activity of lineage-defining transcription factors, erosion of CLL cell identity, and acquisition of a quiescence-like gene signature. We observe patient-to-patient variation in the speed of execution of this program, which we exploit to predict patient-specific dynamics in the response to ibrutinib based on the pre-treatment patient samples. In aggregate, our study describes time-dependent cellular, molecular, and regulatory effects for therapeutic inhibition of B cell receptor signaling in CLL, and it establishes a broadly applicable method for epigenome/transcriptome-based treatment monitoring.

Macrophage-mediated antibody dependent effector function in aggressive B-cell lymphoma treatment is enhanced by Ibrutinib via inhibition of JAK2

“…Finally, Kondo et al could show that ibrutinib treatment of CLL cells also inhibits STAT3 phosphorylation and described suppression of IL10 and PD-L1 in ibrutinib treated CLL patient cells (44). In this line a single cell immune profiling of the temporal dynamics of ibrutinib treatment in CLL patient revealed profound modulation of the non-malignant immune cells and particularly up-regulation of inflammatory pathways in myeloid cells (45). In this context the potential benefits of early phase trials using BTK inhibitors or ruxolitinib in severe COVID-19 patients can be hypothesized to be related to overlapping target specificity and regulation of inflammatory pathways (5,6,46).…”

Macrophage-Mediated Antibody Dependent Effector Function in Aggressive B-Cell Lymphoma Treatment is Enhanced by Ibrutinib via Inhibition of JAK2

“…Finally, Kondo et al could show that ibrutinib treatment of CLL cells also inhibits STAT3 phosphorylation and described suppression of interleukin-10 (IL10) and programmed cell death ligand 1 (PD-L1) in ibrutinib treated CLL patient cells [ 43 ]. In this line a single cell immune profiling of the temporal dynamics of ibrutinib treatment in CLL patient revealed profound modulation of the non-malignant immune cells and particularly up-regulation of inflammatory pathways in myeloid cells [ 44 ]. In this context the potential benefits of early phase trials using BTK inhibitors or ruxolitinib in severe COVID-19 patients can be hypothesized to be related to overlapping target specificity and regulation of inflammatory pathways [ 5 , 6 , 45 ].…”

Application of Artificial Intelligence Technology in Oncology: Towards the Establishment of Precision Medicine

“…The Bruton tyrosine kinase inhibitor ibrutinib is an effective treatment for patients with chronic lymphocytic leukemia (CLL); however, there is extensive heterogeneity in this disease. Rendeiro et al attempted to predict the response to ibrutinib treatment by analyzing multi-layered omics data (immunophenotyping, single-cell RNA-seq, and ATAC-seq) together with clinical information using machine learning techniques [116]. Non-malignant B cell changes reflected changes in the CLL cells, with CD4+ T cells, CD8+ T cells, natural killer (NK) cells, and myeloid cells responding in a cell type-specific manner [116].…”