Abstract
BackgroundIbrutinib, an irreversible Bruton Tyrosine Kinase (BTK) inhibitor, has revolutionized Chronic Lymphocytic Leukemia (CLL) treatment, but resistances to ibrutinib have emerged, whether related or not to BTK mutations. Patterns of CLL evolution under ibrutinib therapy are well characterized for the leukemic cells but not for their microenvironment.MethodsHere, we addressed this question at the single cell level of both transcriptome and immune-phenotype. The PBMCs from a CLL patient were monitored during ibrutinib treatment using Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-Seq) technology.ResultsThis unveiled that the short clinical relapse of this patient driven by BTK mutation is associated with intraclonal heterogeneity in B leukemic cells and up-regulation of common signaling pathways induced by ibrutinib in both B leukemic cells and immune cells. This approach also pinpointed a subset of leukemic cells present before treatment and highly enriched during progression under ibrutinib. These latter exhibit an original gene signature including up-regulated BCR, MYC-activated, and other targetable pathways. Meanwhile, although ibrutinib differentially affected the exhaustion of T lymphocytes, this treatment enhanced the T cell cytotoxicity even during disease progression.ConclusionsThese results could open new alternative of therapeutic strategies for ibrutinib-refractory CLL patients, based on immunotherapy or targeting B leukemic cells themselves.
Highlights
Ibrutinib, an irreversible Bruton Tyrosine Kinase (BTK) inhibitor, has revolutionized Chronic Lymphocytic Leukemia (CLL) treatment, but resistances to ibrutinib have emerged, whether related or not to BTK mutations
B leukemic cells and T lymphocytes were drastically reduced after 3 months of treatment whereas Natural Killer (NK) cells remained stable
Dissecting CLL disease using high-dimensional singlecell technologies is fundamental to a better knowledge of biological features contributing to response to therapy and relapse
Summary
An irreversible Bruton Tyrosine Kinase (BTK) inhibitor, has revolutionized Chronic Lymphocytic Leukemia (CLL) treatment, but resistances to ibrutinib have emerged, whether related or not to BTK mutations. Patterns of CLL evolution under ibrutinib therapy are well characterized for the leukemic cells but not for their microenvironment. Ibrutinib is an irreversible BTK inhibitor and has TEC family kinase off-target effects in immune cells [6, 7]. Ibrutinib targets CLL through different mechanisms occurring mostly in tissues: induction of apoptosis, inhibition of proliferation by disruption of the BCR and NF-kB signaling pathways, impairment of adhesion and migration leading to leukemic cell egress from tissues to blood [8,9,10,11,12,13]. Evolution patterns of CLL before and after ibrutinib therapy have been recently addressed, but, in these studies, lymphocytosis evolution patterns only concerned leukemic cells [17, 18] and must be investigated in the context of CLL microenvironment which is critical for pathogenesis
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