肿瘤细胞治疗研究
英文原题：T-cell immunosenescence limits CD19 CAR T-cell function in chronic lymphocytic leukemia.
这些数据共同表明，免疫衰老是 CLL 中 CAR-T 细胞疗效的一个可测量且具有功能后果的障碍，也是治疗调节的候选靶点。
靶向 CD19 的 CAR-T 细胞（CTL019）可使慢性淋巴细胞白血病（CLL）获得持久缓解，但治疗成功取决于自体 T 细胞在制备后能否扩增、持续存在并保有细胞毒功能。CLL T 细胞功能衰竭通常归因于耗竭，尽管许多功能障碍的 CLL T 细胞仍能产生炎性细胞因子。我们检验这种矛盾是否反映免疫衰老——一种类似衰老的程序，其特征包括共刺激分子丢失、DNA 损伤、炎症性分泌、受体库受限和增殖停滞。在与治疗应答相关的输注前 CTL019 产品中，无应答者和短暂部分应答者的衰老及衰老相关分泌表型（SASP）程序高于功能性应答组；后者包括完全应答者和伴转化疾病的部分应答者。这些程序在输注前即可检测到，并在易感产品的制备过程中进一步增强。其与体内 CAR-T 细胞扩增较弱相关，并伴随较差生存结局。血清蛋白质组学显示，无应答者存在一种与 CLL 相关、类似 SASP 的循环炎症环境。流式细胞术和 TCR 分析显示，疗效不佳者在单采时携带 CD27−CD28− 和 KLRG1+ CD8 T 细胞，产品中 CD27 表达较低且 TCR 多样性下降。由未经治疗的 CLL 样本研究性制备的 CAR-T 细胞也呈现相同状态，其中 CD4 CAR-T 细胞最为明显，表现为 SA-β-gal、p16、p53 和 DNA 损伤增加、低分化状态细胞减少及富集免疫衰老特征的转录组。反复接受 CD19 刺激后，CLL 来源产品出现增殖上限；p53 高表达产品的细胞毒储备下降。伊布替尼在配对患者样本和直接暴露实验中改善增殖适能、减轻免疫衰老相关特征及 SASP 产出，并在伊布替尼耐药的 CLL 模型中增强 CAR-T 细胞扩增。综上，免疫衰老是影响 CLL CAR-T 疗效、可测量且具有功能后果的障碍，也可能成为可干预的治疗靶点。
CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27 CD28 and KLRG1 CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-na ve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA- -gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.
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