肿瘤细胞治疗研究
英文原题：Liposomal Oncolytic Adenovirus Enables Efficient CAR-Independent Transduction of Tumors and Enhances NK Cell-Mediated Abscopal Responses.
这些发现揭示了NK细胞在介导腺病毒诱导的远隔效应中一个此前未被认识的作用，并将DfA定位为针对CAR缺陷肿瘤的一种临床上可行的策略。
有效递送溶瘤腺病毒至低表达柯萨奇病毒和腺病毒受体（CAR）的肿瘤，仍是溶瘤病毒治疗中的主要障碍。本研究设计了一种脂质体包裹的基于5型腺病毒的平台（DfA），以绕过CAR依赖性转导，并以固有免疫、NK细胞依赖的方式呈现引人关注的抗肿瘤免疫应答。结果表明，DfA可高效转导CAR低表达的小鼠结直肠癌细胞（CT26），并触发损伤相关分子模式（DAMPs）的释放，包括ATP、HMGB1和钙网蛋白。在免疫健全小鼠中，瘤内DfA治疗抑制了局部和远处肿瘤生长。在缺乏T细胞的裸鼠中，DfA保留了全身抗肿瘤活性，但NK细胞耗竭后远隔效应消失，这提示自然杀伤（NK）细胞是此应答的必要介质。在体外，DfA增强了NK92对低CAR MCF-7乳腺癌细胞的细胞毒性，进一步支持其固有免疫激活潜力。总之，这些发现揭示了NK细胞在介导腺病毒诱导的远隔效应中此前未被认识的作用，并将DfA定位为一种可用于CAR缺陷肿瘤的临床可行策略。
Effective delivery of oncolytic adenoviruses to tumors with low coxsackievirus and adenovirus receptor (CAR) expression remains a major barrier in oncolytic virotherapy. In this study, a liposome-encapsulated adenovirus serotype 5-based platform (DfA) was designed to bypass CAR-dependent transduction, presenting engaging antitumor immune responses in an innate immune, NK cell-dependent manner. The results show that DfA efficiently transduces CAR-low murine colorectal cancer cells (CT26) and triggers the release of damage-associated molecular patterns (DAMPs), including ATP, HMGB1, and calreticulin. In immunocompetent mice, intratumoral DfA treatment suppressed both local and distant tumor growth. In nude mice lacking T cells, DfA retained systemic antitumor activity, but abscopal effects were lost upon NK cell depletion, which suggests that natural killer (NK) cells are essential mediators of this response. In vitro, DfA enhanced NK92 cytotoxicity against low-CAR MCF-7 breast cancer cells, which further supports its innate immune-activating potential. Together, these findings reveal a previously unrecognized role for NK cells in mediating adenovirus-induced abscopal effects and position DfA as a clinically actionable strategy for CAR-deficient tumors.
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