Epitranscriptomics modifier pentostatin indirectly triggers Toll-like receptor 3 and can enhance immune infiltration in tumors,Molecular Therapy

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Epitranscriptomics modifier pentostatin indirectly triggers Toll-like receptor 3 and can enhance immune infiltration in tumors
Molecular Therapy ( IF 12.1 ) Pub Date : 2021-09-24 , DOI: 10.1016/j.ymthe.2021.09.022
Marina Tusup ₁ , Thomas M Kündig ₂ , Steve Pascolo ₂

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The adenosine deaminase inhibitor 2′-deoxycoformycin (pentostatin, Nipent) has been used since 1982 to treat leukemia and lymphoma, but its mode of action is still unknown. Pentostatin was reported to decrease methylation of cellular RNA. We discovered that RNA extracted from pentostatin-treated cells or mice has enhanced immunostimulating capacities. Accordingly, we demonstrated in mice that the anticancer activity of pentostatin required Toll-like receptor 3, the type I interferon receptor, and T cells. Upon systemic administration of pentostatin, type I interferon is produced locally in tumors, resulting in immune cell infiltration. We combined pentostatin with immune checkpoint inhibitors and observed synergistic anti-cancer activities. Our work identifies pentostatin as a new class of an anticancer immunostimulating drug that activates innate immunity within tumor tissues and synergizes with systemic T cell therapies.

中文翻译：

表观转录组学修饰剂喷司他丁间接触发Toll样受体3并可增强肿瘤中的免疫浸润

腺苷脱氨酶抑制剂2'-脱氧考福霉素（喷司他丁，Nipent）自1982年以来一直用于治疗白血病和淋巴瘤，但其作用方式仍不清楚。据报道喷司他丁可减少细胞 RNA 的甲基化。我们发现从喷司他丁处理的细胞或小鼠中提取的 RNA 具有增强的免疫刺激能力。因此，我们在小鼠中证明喷司他丁的抗癌活性需要 Toll 样受体 3、I 型干扰素受体和 T 细胞。全身给予喷司他丁后，肿瘤局部产生 I 型干扰素，导致免疫细胞浸润。我们将喷司他丁与免疫检查点抑制剂联合使用，并观察到协同抗癌活性。我们的工作将喷司他丁确定为一类新型抗癌免疫刺激药物，可激活肿瘤组织内的先天免疫并与全身 T 细胞疗法产生协同作用。

更新日期：2021-09-24

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