肿瘤细胞治疗研究
英文原题：Adaptive-like CAR-iPSC-CD4⁺ T cells outperform CD8⁺ counterparts in sustained ALL control.
尽管与原发性 CD4 T 细胞不完全相同，iPSC 衍生的 CD4 T 细胞重现了关键功能优势，尤其是持续的抗肿瘤活性，支持其作为下一代 CAR-T 治疗的可再生、现货型来源的价值。
背景：诱导多能干细胞（iPSC）来源T细胞为现货型免疫治疗提供可再生来源。随着人工胸腺类器官（ATO）方法出现，体外由iPSC分化CD4⁺ T细胞也已成为可能。原代CD4⁺ T细胞具有持久性更强、较不易耗竭和辅助功能突出等特点，但iPSC来源CD4⁺ T细胞是否保留这些特征仍不明确。方法：本研究使用ATO系统将人iPSC分化为CD4⁺ T细胞，并以原代T细胞为对照评估iPSC来源CD4⁺和CD8⁺ T细胞表型及活化特征。为评估抗肿瘤功能，构建CD19-BB CAR-iPSC-T细胞，并采用NALM6急性淋巴细胞白血病（ALL）模型。通过短期和长期细胞毒性实验，比较iPSC来源CD4⁺与CD8⁺ T细胞的杀伤效率、细胞因子分泌、持久性、耗竭表型和增殖能力。还通过Ki-67染色和增殖实验评估iPSC来源CD4⁺ T细胞对CD8⁺ T细胞的辅助作用。结果：iPSC来源CD4⁺ T细胞同时呈现辅助和细胞毒样特征。CAR转导后，与iPSC来源CD8⁺ T细胞或CD4⁺/CD8⁺混合物相比，iPSC来源CD4⁺ T细胞增殖更强、细胞因子分泌更多，且细胞毒作用更持久；它们还能促进iPSC来源CD8⁺ T细胞扩增，并表现出类似辅助细胞的功能及较强抗耗竭能力。结论：尽管iPSC来源CD4⁺ T细胞与原代CD4⁺ T细胞并非完全相同，但保留了关键功能优势，尤其是持久抗肿瘤活性，支持其作为下一代CAR-T疗法可再生现货型来源的价值。
BACKGROUND: Induced pluripotent stem cell (iPSC)-derived T cells offer a renewable source for off-the-shelf immunotherapy. With the advent of the artificial thymic organoid (ATO) method, the in vitro differentiation of CD4 + T cells from iPSCs has also become feasible. CD4 T cells have shown superior longevity, resistance to exhaustion, and helper functions in primary settings, but whether iPSC-derived CD4 T cells retain these features remains unclear. METHODS: In this study, CD4 T cells were differentiated from human iPSCs using the ATO system. Primary T cells served as controls to evaluate the phenotypic and activation features of iPSC-derived CD4 and CD8 T cells. To assess antitumor function, we generated CD19-BB CAR-iPSC-T cells and employed a hematologic malignancy model using NALM6 acute lymphoblastic leukemia (ALL) cells. Both short-term and long-term cytotoxicity assays were conducted to compare iPSC-derived CD4 and CD8 T cells in terms of killing efficiency, cytokine secretion, persistence, exhaustion phenotype, and proliferative capacity. The helper function of iPSC-derived CD4 T cells toward CD8 T cells was further evaluated by Ki-67 staining and proliferation assays. Statistical analyses were performed using GraphPad Prism. RESULTS: Our study demonstrated that iPSC-derived CD4 T cells exhibited both helper- and cytotoxic-like features. Compared with iPSC-derived CD8 T cells or CD4 /CD8 mixtures, iPSC-derived CD4 T cells showed superior proliferation, cytokine secretion, and sustained cytotoxicity following CAR transduction. They also promoted the expansion of iPSC-derived CD8 T cells and displayed helper-like functions with increased resistance to exhaustion. CONCLUSIONS: Although not identical to primary CD4 T cells, iPSC-derived CD4 T cells recapitulated key functional advantages, especially sustained antitumor activity, supporting their value as a renewable, off-the-shelf source for next-generation CAR-T therapies.
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