Effective antitumor T cell activity relies on the expression and MHC presentation of tumor neoantigens. Tumor cells can evade T cell detection by silencing the transcription of antigens or by altering MHC machinery resulting in inadequate neoantigen-specific T cell activation. We identified DNA-PK inhibitor (DNA-PKi) NU7441 as a promising immunomodulator that reduced immunosuppressive proteins while increasing MHC-I expression in a panel of human melanoma cell lines. In tumor-bearing mice, combination therapy using NU7441 and immune adjuvants STING ligand and CD40 agonist (NU-SL40) substantially increased and diversified the neoantigen landscape, antigen presenting machinery, and consequently substantially increased both the number and repertoire of neoantigen-reactive tumor infiltrating lymphocytes (TILs). DNA-PK-inhibition or knockout promoted transcription and protein expression of various neoantigens in human and mouse melanomas and induced sensitivity to ICB in resistant tumors. In patients, PRKDC levels inversely correlated with MHC I expression and CD8 TILs but positively correlated with increased neoantigen loads and improved responses to ICB. These studies suggest that inhibiting DNA-PK activity can restore tumor immunogenicity by increasing neoantigen expression and presentation and broadening the neoantigen-reactive T cell population.

中文翻译：

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DNA-PK 抑制增强了新抗原多样性并增加了 T 细胞对免疫耐药肿瘤的反应。


有效的抗肿瘤 T 细胞活性取决于肿瘤新抗原的表达和 MHC 呈递。肿瘤细胞可以通过沉默抗原转录或通过改变 MHC 机制导致新抗原特异性 T 细胞激活不足来逃避 T 细胞检测。我们确定 DNA-PK 抑制剂 （DNA-PKi） NU7441 是一种很有前途的免疫调节剂，可减少免疫抑制蛋白，同时增加一组人黑色素瘤细胞系中的 MHC-I 表达。在荷瘤小鼠中，使用 NU7441 和免疫佐剂 STING 配体和 CD40 激动剂 （NU-SL40） 的联合治疗显着增加和多样化新抗原景观、抗原呈递机制，因此显着增加了新抗原反应性肿瘤浸润淋巴细胞 （TIL） 的数量和库。DNA-PK 抑制或敲除促进人和小鼠黑色素瘤中各种新抗原的转录和蛋白表达，并诱导耐药性肿瘤对 ICB 的敏感性。在患者中，PRKDC 水平与 MHC I 表达和 CD8 TILs 呈负相关，但与新抗原载量增加和对 ICB 反应的改善呈正相关。这些研究表明，抑制 DNA-PK 活性可以通过增加新抗原表达和呈递以及扩大新抗原反应性 T 细胞群来恢复肿瘤免疫原性。