内源性逆转录病毒（ERV）元素是人类基因组中古老逆转录病毒感染的基因遗迹。以往的研究已经证明，ERV转录水平的失调与癌症中的免疫细胞浸润有关，但ERV表达与PD-1阻断治疗在实体肿瘤（如晚期透明细胞肾细胞癌）中的反应关系尚未被揭示。本研究获取了参与接受抗PD-1治疗的晚期透明细胞肾细胞癌临床试验的ERV mRNA表达数据（CM-009、CM-010、CM-025和TCGA-KIRC数据）。将接受尼伐木单抗治疗的患者分为训练集和验证集，TCGA-KIRC数据集作为外部验证。通过单变量Cox回归分析和最小绝对收缩和选择算子回归分析建立标志特征。进行免疫细胞浸润分析和基因集富集分析以探索潜在的生物学机制。在九种ERV表达模式的基础上建立了ERV标志特征。在训练集中，低风险组和高风险组的中位总生存期分别为45.2个月和19.6个月（风险比（HR）= 0.49，0.32-0.75，p < 0.001）。这些结果在验证集（HR = 0.41，0.20-0.83，p = 0.013）以及TCGA-KIRC数据集（HR = 0.55，0.34-0.90，p = 0.017）中得到了证实。此外，在CM-025数据集中，低风险组接受尼伐木单抗治疗的患者比接受mTOR抑制剂依维莫司的患者有更好的生存情况，而高风险组没有观察到显著差异。低风险组富含CD8+ T细胞，同时免疫抑制途径被抑制。新发现的ERV标志既是晚期透明细胞肾细胞癌患者的预后标志，也是抗PD-1治疗的预测标志，可为未来癌症患者个体化治疗指导提供参考。©作者（们），2022年。

Endogenous retrovirus (ERV) elements are genomic footprints of ancestral retroviral infections within the human genome. Previous studies have demonstrated that dysregulated ERV transcription level is associated with immune cell infiltration in cancers, but the association between ERV expression and programmed cell death protein 1 (PD-1) blockade response is currently unraveled for solid cancers, such as advanced clear cell renal cell carcinoma (ccRCC).ERV mRNA profiles were obtained from three clinical trials of ccRCC where the patients were treated with anti-PD-1 (CM-009, CM-010, CM-025, and TCGA-KIRC data). Patients treated with nivolumab were divided into training and test cohort, while the TCGA-KIRC cohort was used as an external validation. Univariate Cox regression analysis and least absolute shrinkage and selection operator regression were used to establish the signature. Immune cell infiltration analysis and gene set enrichment analysis were performed to explore potential biological mechanisms.An ERV signature was established based on nine ERV expression patterns. In the training cohort, the median overall survival in the low- and high-risk group was 45.2 and 19.6 months [hazard ratio (HR) = 0.49, 0.32-0.75, p < 0.001], respectively. The results were confirmed in the test (HR = 0.41, 0.20-0.83, p = 0.013), and in the TCGA-KIRC cohort (HR = 0.55, 0.34-0.90, p = 0.017). Moreover, in the CM-025 cohort, the low-risk group that received nivolumab had a more favorable survival compared with those that received the mTOR inhibitor everolimus, while no significant differences were observed in the high-risk group. CD8+ T cells were enriched in the low-risk group, while immune suppressive pathways were suppressed.The newly identified ERV signature is not only a prognostic, but also a predictive biomarker for advanced ccRCC patients who received anti-PD-1 therapy, which can guide personalized treatment in cancer patients in the future.© The Author(s), 2022.