Chimeric antigen receptor (CAR) T cell therapy has exhibited dramatic anti-tumor efficacy in clinical trials. In this study, we reported the transcriptome profiles of bone marrow cells in four B cell acute lymphoblastic leukemia (B-ALL) patients before and after CD19-specific CAR-T therapy. CD19-CAR-T therapy remarkably reduced the number of leukemia cells, and three patients achieved bone marrow remission (minimal residual disease negative). The efficacy of CD19-CAR-T therapy on B-ALL was positively correlated with the abundance of CAR and immune cell subpopulations, e.g., CD8+ T cells and natural killer (NK) cells, in the bone marrow. Additionally, CD19-CAR-T therapy mainly influenced the expression of genes linked to cell cycle and immune response pathways, including the NK cell mediated cytotoxicity and NOD-like receptor signaling pathways. The regulatory network analyses revealed that microRNAs (e.g., miR-148a-3p and miR-375), acting as oncogenes or tumor suppressors, could regulate the crosstalk between the genes encoding transcription factors (TFs; e.g., JUN and FOS) and histones (e.g., HIST1H4A and HIST2H4A) involved in CD19-CAR-T therapy. Furthermore, many long non-coding RNAs showed a high degree of co-expression with TFs or histones (e.g., FOS and HIST1H4B) and were associated with immune processes. These transcriptome analyses provided important clues for further understanding the gene expression and related mechanisms underlying the efficacy of CAR-T immunotherapy.
B细胞急性淋巴细胞白血病（B-ALL）是由于B细发育异常，细胞凋亡逃避和不受控制的细胞增殖所引起的。在传统放化疗疗效不佳的情况下，通过改造后靶向B细胞恶性肿瘤特异性抗原CD19的嵌合抗原受体（CAR）T细胞（CD19-CAR-T）被认为是B-ALL免疫疗法中最有希望的方法。CD19-CAR-T可以识别和消除肿瘤细胞，并且已证实对复发/难治性B-ALL患者的缓解有显着功效。目前大多数关于CAR-T免疫疗法的研究都集中在临床疗效评估和新抗原的发展上，缺少对CAR-T治疗后患者基因表达和调控机制的研究。本研究报道了4例B-ALL患者接受CD19-CAR-T治疗前后骨髓细胞的转录组图谱。临床检测显示CD19-CAR-T治疗后，患者白血病细胞的数量显著减少，并且实现了3名患者的骨髓缓解（微小残留病阴性）。研究发现，CD19-CAR-T治疗B-ALL的疗效与骨髓中CAR细胞和部分免疫细胞亚群（例如CD8+ T细胞和自然杀伤（NK）细胞）的丰度成正相关。另外，CD19-CAR-T疗法影响了大量与细胞周期和免疫应答通路相关基因的表达，包括参与NK细胞介导的细胞毒性和NOD样受体信号传导等通路基因。调控网络分析显示，重要microRNA（如miR-148a-3p和miR-375）可以通过调控转录因子基因（如JUN和FOS）以及组蛋白基因（如HIST1H4A和HIST2H4A）的表达而参与CD19-CAR-T治疗调控。此外，许多长非编码RNA与转录因子或组蛋白基因高度共表达而参与免疫过程。这些转录组表达和调控分析为进一步了解CAR-T免疫治疗疗效的相关机制提供了重要线索。





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