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. Patterns of CLL evolution under ibrutinib therapy are well characterized for the leukemic cells but not for their microenvironment. Here, 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. This 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. These results could open new alternative of therapeutic strategies for ibrutinib-refractory CLL patients, based on immunotherapy or targeting B leukemic cells themselves.

中文翻译：

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依鲁替尼治疗期间慢性淋巴细胞白血病的纵向 CITE-Seq 分析：复发时白血病细胞和免疫细胞的进化


依鲁替尼是一种不可逆的布鲁顿酪氨酸激酶 (BTK) 抑制剂，彻底改变了慢性淋巴细胞白血病 (CLL) 的治疗，但对依鲁替尼的耐药性已经出现，无论是否与 BTK 突变有关。依鲁替尼治疗下 CLL 的演变模式对白血病细胞有很好的特征，但对其微环境却没有。在这里，我们在转录组和免疫表型的单细胞水平上解决了这个问题。在依鲁替尼治疗期间，使用转录组和表位细胞索引测序 (CITE-Seq) 技术对 CLL 患者的 PBMC 进行监测。这揭示了该患者由 BTK 突变驱动的短期临床复发与 B 白血病细胞的克隆内异质性以及依鲁替尼在 B 白血病细胞和免疫细胞中诱导的常见信号通路的上调有关。这种方法还精确定位了治疗前存在的白血病细胞子集，以及在依鲁替尼治疗期间高度富集的白血病细胞子集。后者表现出原始基因特征，包括上调的 BCR、MYC 激活和其他可靶向途径。同时，尽管依鲁替尼对 T 淋巴细胞的耗竭有不同的影响，但这种治疗即使在疾病进展期间也增强了 T 细胞的细胞毒性。这些结果可能为依鲁替尼难治性 CLL 患者开辟新的治疗策略替代方案，基于免疫疗法或靶向 B 白血病细胞本身。