Allison Joy Nielsen,Gabriella Kyra Albert,Amelia Sanchez,Jiangli Chen,Jing Liu,Andres Sebastian Davalos,Degui Geng,Xander G Bradeen,Jennifer D Hintzsche,William Robinson,Martin McCarter,Carol M Amato,Richard Tobin,Kasey L Couts,Breelyn Ann Wilky,Eduardo Davila
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引用次数: 0
摘要
有效的抗肿瘤 T 细胞活性依赖于肿瘤新抗原的表达和 MHC 呈递。肿瘤细胞可以通过抑制抗原转录或改变 MHC 机制来逃避 T 细胞检测,从而导致新抗原特异性 T 细胞活化不足。我们发现DNA-PK抑制剂(DNA-PKi)NU7441是一种很有前景的免疫调节剂,它能减少免疫抑制蛋白,同时增加人类黑色素瘤细胞系的MHC-I表达。在肿瘤小鼠中,使用 NU7441 和免疫佐剂 STING 配体及 CD40 激动剂(NU-SL40)进行联合治疗,可显著增加新抗原的分布和抗原递呈机制的多样性,从而大幅增加新抗原反应性肿瘤浸润淋巴细胞(TILs)的数量和种类。DNA-PK 抑制或基因敲除可促进人和小鼠黑色素瘤中各种新抗原的转录和蛋白表达,并诱导耐药肿瘤对 ICB 敏感。在患者中,PRKDC水平与MHC I表达和CD8 TILs成反比,但与新抗原负荷的增加和对ICB反应的改善成正比。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现以及扩大新抗原反应性 T 细胞群来恢复肿瘤免疫原性。
DNA-PK inhibition enhances neoantigen diversity and increases T cell responses to immunoresistant tumors.
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.