肿瘤细胞治疗研究
英文原题：CXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting.
CXCR4 induces memory formation over exhaustion in CAR-T cells to achieve durable leukemia targeting.
我们的结果表明，CXCR4 可增强 CAR-T 细胞的记忆与持久性，为改善 AML 及更广泛疾病的免疫治疗结局提供了一种策略。
嵌合抗原受体（CAR）T细胞疗法改变了B细胞恶性肿瘤的治疗，但其治疗急性髓系白血病（AML）的成功仍有限。持久应答依赖长寿命记忆T细胞的形成，而T细胞耗竭会导致无应答和复发。我们首先观察到，在脐带血移植后达到缓解的AML患者中，高表达趋化因子受体CXCR4的记忆T细胞富集。随后，我们证明，通过工程化改造使CAR-T细胞共同表达CXCR4，可在患者来源异种移植模型中增强其持久性和抗白血病活性。利用单细胞分析和代谢分析，我们发现CXCR4可促进记忆相关转录程序、减少耗竭并支持氧化代谢。上述效应见于靶向AML相关靶点CD25或CD96的CAR-T细胞。我们的研究结果表明，CXCR4可增强CAR-T细胞记忆性和持久性，为改善AML及其他疾病免疫治疗结局提供一种策略。
Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of B-cell malignancies, but its success in acute myeloid leukemia (AML) remains limited. Durable responses depend on the formation of long-lived memory T cells, whereas T cell exhaustion contributes to non-response and relapse. In patients with AML who achieved remission after cord blood transplantation, we here first observe enrichment of memory T cells with high expression of the chemokine receptor CXCR4. Next, we show that engineering CAR-T cells to co-express CXCR4 enhances their persistence and anti-leukemic activity in patient-derived xenograft models. Using single-cell profiling and metabolic analysis, we find that CXCR4 promotes memory-associated transcriptional programs, reduces exhaustion, and supports oxidative metabolism. These effects are observed with CAR-T cells targeting CD25 or CD96 as AML-associated targets. Our results indicate that CXCR4 strengthens CAR-T cell memory and durability, offering a strategy to improve immunotherapy outcomes in AML and beyond.
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