肿瘤细胞治疗研究
英文原题：Preclinical efficacy of iPSC-derived MUC1-targeted CAR-NK cells against esophageal squamous cell carcinoma.
iPSC来源的MUC1靶向CAR-NK细胞对人ESCC发挥强效且特异性的抗肿瘤作用，支持这种现货型细胞疗法的临床转化。
MUC1在食管鳞状细胞癌（ESCC）中频繁过表达，但靶向MUC1的CAR-NK细胞在该恶性肿瘤中尚未被探索。
MUC1 表达通过 IHC 在 90 例 ESCC 标本、47 例配对的癌旁正常组织以及正常人器官中进行评估。MUC1 靶向 CAR-NK 细胞由 iPSC 平台生成。使用 live/dead 染色、CCK-8 和 xCELLigence 检测，针对患者特异性 ESCC 类器官（PSO）、原代 ESCC 细胞、KYSE150 和 KYSE140 细胞评估抗肿瘤活性。在 KYSE140 异种移植模型中评估体内疗效。
MUC1 在 70%（63/90）的 ESCC 病例中表达，而在癌旁正常组织中为 14.9%（7/47）（P < 0.001），在正常器官中表达可忽略不计。在 MUC1 阳性 ESCC 中，分别有 88.9% 和 42.8% 显示 > 50% 和 > 80% 的肿瘤细胞阳性。iPSC 来源的 MUC1 CAR-NK 细胞在 iPSC、祖细胞和成熟阶段均表现出 > 95% 的 CAR 表达。与对照相比，MUC1 CAR-NK 细胞在体外对表达 MUC1 的 ESCC PSO、原代细胞、KYSE150 和 KYSE140 产生强效的抗原特异性细胞毒性，并在体内显著抑制 KYSE140 异种移植瘤生长。
BACKGROUND: MUC1 is frequently overexpressed in esophageal squamous cell carcinoma (ESCC), but MUC1-targeted CAR-NK cells remain unexplored in this malignancy. METHODS: MUC1 expression was assessed by IHC in 90 ESCC specimens, 47 paired adjacent normal tissues, and normal human organs. MUC1-targeted CAR-NK cells were generated from an iPSC platform. Antitumor activity was evaluated against patient-specific ESCC organoids (PSOs), primary ESCC cells, KYSE150 and KYSE140 cells using live/dead staining, CCK-8, and xCELLigence assays. In vivo efficacy was assessed in a KYSE140 xenograft model. RESULTS: MUC1 was expressed in 70% (63/90) of ESCC cases versus 14.9% (7/47) of adjacent normal tissues (P < 0.001), with negligible expression in normal organs. Among MUC1-positive ESCCs, 88.9% and 42.8% showed > 50% and > 80% tumor cell positivity, respectively. iPSC-derived MUC1 CAR-NK cells exhibited > 95% CAR expression across iPSC, progenitor, and mature stages. Compared with controls, MUC1 CAR-NK cells elicited potent, antigen-specific cytotoxicity against MUC1-expressing ESCC PSOs, primary cells, KYSE150, and KYSE140 in vitro and significantly suppressed KYSE140 xenograft growth in vivo. CONCLUSION: iPSC-derived MUC1-targeted CAR-NK cells exert robust and specific antitumor efficacy against human ESCC, supporting clinical translation of this off-the-shelf cell therapy.
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