BER失衡超载DNA突变负荷决定肺癌抗PD-1治疗反应及其机制的研究

Immunocheckpoint blockade, including anti-PD-1 therapy has raised hope for thetreatment of advanced lung cancer. With the objective response rate of merely 17-21%, a predictive marker for effectiveness is in desperate need. Newly reports demonstrated a promising predictive role of overload of genome mutational burden in effectiveness of anti-PD-1 therapeutics, while the lack of understanding of mechanisms restricted the clinical applications. We previously found that the positive correlations between anti-PD-1 efficacy and the deficiencies of key.enzymes in base excision repair (BER) responsive for the restore the lesion of abasic sites, downregulation of APE1 and/or downregulation of DNA polymerase β in lung cancer patients. With regards of the biochemically “passing the baton” model of BER, we hypothesized that the imbalance of BER causes the exposure of unrepaired abasic sites which further arises genomic mutational rates. The current project will employ the tissue samples from clinical biological bank, DNA biochemical assays and cancer cells/lymphocytes co-culture models to elucidate the role and detailed mechanisms of BER imbalance in overload of mutational burden, with hope to discover the key molecules in predicting anti-PD-1 therapeutic efficacy and possible targeting strategy in promoting immunotherapy efficacy in lung cancer.

免疫检查点阻断剂如抗PD-1为晚期肺癌的治疗带来了新希望，但其有效率仅为17-21%，虽然基因组突变负荷超载对预测抗PD-1的疗效具有重要价值，然而机制尚不清楚。我们前期研究发现负责修复缺碱基（AP）位点的碱基切除修复（BER）中的限速酶APE1和/或DNA合成酶β在肺癌组织中的表达缺陷与抗PD-1的疗效密切相关。基于BER修复途径的“接力棒”特性，我们推测BER失衡可能是大量AP位点不能修复，进而引起突变负荷增加的重要机制，而APE1和DNA合成酶β在BER失衡中可能具有关键作用。本研究通过肺癌临床标本数据库、DNA生化实验以及肿瘤细胞/淋巴细胞共培养模型等技术，旨在揭示BER失衡在超载基因组高突变负荷中的作用及其分子机制，以期发现预测抗PD-1治疗反应的关键分子，同时进一步探索可能的提高肺癌免疫治疗的有效策略。

免疫检查点抑制剂（ICIs）治疗如PD-1单抗为肿瘤治疗带来了新的希望，而ICIs低响应性的特点促使我们去寻找合适的生物标志物来预测疗效，并探索提高ICIs疗效的可能机制。碱基切除修复（BER）的关键酶APE1在肺癌组织中的表达缺陷与ICIs疗效密切相关，而其中的机制并不清楚，微环境的改变也尚未明晰。缺碱基（AP）位点的跨损伤复制（Translesion synthesis，TLS）跨越（bypass）修复失败可导致突变的积累，突变负荷的增加，进而造成新生抗原的数量和质量的提升，可能是改善免疫状态，增强ICIs疗效的关键因素之一。同时，ICIs的治疗疗效与免疫微环境密切相关，解析APE1表达情况与免疫微环境的关系可以为精确联用APE1抑制剂与ICIs提供指导。本研究发现，APE1与CD4+T细胞的浸润呈负相关。在APE1低表达组中，CD4+T细胞越多，患者预后越好，在APE1高表达组中，CD4+T细胞与预后无关。提示我们联合分析APE1的表达情况与肿瘤微环境中的浸润情况对精准预测患者的预后和ICIs疗效具有重要的意义。同时，CD8+T细胞、B细胞在APE1高表达组丰度低，而Treg细胞和DC数量在APE1高表达组丰度高。进一步分析发现APE1的表达水平与代表耗竭型的C5群CD8+ T细胞和中间型C2群CD8+ T细胞呈正相关；综上，APE1表达越高，肿瘤免疫微环境越是抑制状态。靶向BER通路的关键酶APE1可能是改善肿瘤免疫，提高ICIs治疗疗效的重要方法。

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