肿瘤细胞治疗研究
英文原题：Broadening activity of checkpoint blockade agents by intratumoral nucleoside cleavage.
Broadening activity of checkpoint blockade agents by intratumoral nucleoside cleavage.
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我们研究了通过聚焦基因治疗破坏恶性细胞及相关肿瘤微环境（TME）是否能拓宽免疫检查点抑制剂（ICI）的疗效。
我们研究了通过局部基因治疗破坏恶性细胞及相关肿瘤微环境（TME）是否能拓宽免疫检查点抑制剂（ICI）的疗效。我们发现，当使用治疗性转基因（嘌呤核苷磷酸化酶，此处称为大肠杆菌PNP）将氟达拉滨（2-氟-阿拉伯呋喃糖基腺嘌呤）切割为抗癌嘌呤碱基2-氟腺嘌呤（F-Ade）时，ICI对同系（小鼠）三阴性乳腺癌（TNBC）的抗肿瘤活性得到增强。我们还证实，采用相同策略治疗的解剖学上远处的、非PNP表达的肿瘤受到强烈抑制。TNBC的细胞减灭与瘤内PD1+ Tregs减少、颗粒酶B+ NK细胞增加、MKI67+ T8细胞升高以及快速免疫清除相关。由于F-Ade的作用机制是破坏微环境中静止的肿瘤细胞和支持细胞，且对ICI的耐药性依赖于完整的TME，因此通过该方法杀伤肿瘤提供了一种使难治性恶性肿瘤对免疫消融敏感的手段，并指向对多种癌症亚型的广泛适用性。
We investigated whether destroying malignant cells and the associated tumor microenvironment (TME) by focal gene therapy would broaden immune checkpoint inhibitor (ICI) effectiveness. We show that ICI antitumor activity against syngeneic (murine) triple-negative breast cancer (TNBC) was augmented when a therapeutic transgene (purine nucleoside phosphorylase, referred to here as E. coli PNP) was used to cleave fludarabine (2-fluoro-arabinofuranosyl adenine) to the anticancer purine base, 2-fluoroadenine (F-Ade). We also established strong repression of anatomically distant, non-PNP-expressing tumors being treated by the same strategy. TNBC cytoreduction was associated with decreased intratumoral PD1+ Tregs, increased granzyme B+ NK cells, elevated MKI67+ T8 cells, and rapid immune clearance. Because F-Ade works by a mechanism that destroys quiescent neoplastic and supporting cells in the microenvironment, and since resistance to ICIs depends upon an intact TME, tumor killing by this approach offers a means to sensitize refractory malignancies to immune ablation and points to broad applicability against numerous cancer subtypes.
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