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Transient activation of tumoral DNA damage tolerance pathway coupled with immune checkpoint blockade exerts durable tumor regression in mouse melanoma
Pigment Cell & Melanoma Research ( IF 3.9 ) Pub Date : 2020-10-30 , DOI: 10.1111/pcmr.12943
Ming Zhuo 1 , Falih M Gorgun 1 , Douglas S Tyler 1 , Ella W Englander 1
Affiliation  

Major advances in cancer therapy rely on engagement of the patient’s immune system and suppression of mechanisms that impede the antitumor immune response. Among the most notable is immune checkpoint blockade (ICB) therapy that releases immune cells from suppression. Although ICB has had significant success particularly in melanoma, it eradicates tumors in subsets of patients and sequencing data across different cancers suggest that tumors with high mutational loads are more likely to respond to ICB. This is consistent with the premise that greater tumoral mutational loads contribute to formation of neoantigens that spur the body’s antitumor immune response. Prompted by strong evidence supporting the therapeutic benefits of neoantigens in the context of ICB, we have developed a mouse melanoma combination treatment, where intratumoral administration of DNA‐damaging drug transiently activates intrinsic mutagenic DNA damage tolerance pathway and improves success rates of ICB. Using the YUMM1.7 cells melanoma model, we demonstrate that intratumoral delivery of cisplatin activates translesion synthesis DNA polymerases‐catalyzed DNA synthesis on damaged DNA, which when coupled with ICB regimen, elicits durable tumor regression. We expect that this new combination protocol affords insights with clinical relevance that will help expand the range of patients who benefit from ICB therapy.

中文翻译:

肿瘤 DNA 损伤耐受通路的瞬时激活与免疫检查点阻断相结合在小鼠黑色素瘤中发挥持久的肿瘤消退作用

癌症治疗的主要进展依赖于患者免疫系统的参与和抑制阻碍抗肿瘤免疫反应的机制。其中最值得注意的是免疫检查点阻断 (ICB) 疗法,该疗法可将免疫细胞从抑制状态中释放出来。尽管 ICB 特别在黑色素瘤方面取得了显着成功,但它可以根除部分患者中的肿瘤,并且不同癌症的测序数据表明,具有高突变负荷的肿瘤更有可能对 ICB 有反应。这与更大的肿瘤突变负荷有助于形成刺激身体抗肿瘤免疫反应的新抗原的前提是一致的。在强有力的证据支持新抗原在 ICB 的背景下的治疗益处的推动下,我们开发了一种小鼠黑色素瘤联合治疗,其中DNA损伤药物的瘤内给药瞬时激活内在诱变DNA损伤耐受途径并提高ICB的成功率。使用 YUMM1.7 细胞黑色素瘤模型,我们证明顺铂的瘤内递送激活跨病灶合成 D​​NA 聚合酶催化受损 DNA 上的 DNA 合成,当与 ICB 方案结合时,可引起持久的肿瘤消退。我们希望这种新的组合方案能够提供具有临床相关性的见解,这将有助于扩大从 ICB 治疗中受益的患者范围。我们证明,顺铂的瘤内递送激活跨病灶合成 D​​NA 聚合酶催化受损 DNA 上的 DNA 合成,当与 ICB 方案结合时,可引起持久的肿瘤消退。我们希望这种新的组合方案能够提供具有临床相关性的见解,这将有助于扩大从 ICB 治疗中受益的患者范围。我们证明,顺铂的瘤内递送激活跨病灶合成 D​​NA 聚合酶催化受损 DNA 上的 DNA 合成,当与 ICB 方案结合时,可引起持久的肿瘤消退。我们希望这种新的组合方案能够提供具有临床相关性的见解,这将有助于扩大从 ICB 治疗中受益的患者范围。
更新日期:2020-10-30
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