Pan-cancer analysis reveals homologous recombination deficiency score as a predictive marker for immunotherapy responders
Pan-cancer analysis reveals homologous recombination deficiency score as a predictive marker for immunotherapy responders
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泛癌分析揭示同源重组缺陷评分可作为免疫治疗反应者的预测标记
DOI：
10.1007/s13577-021-00630-z
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发表时间：
2021-10-10
期刊：
影响因子：
4.3
通讯作者：
Wu, Zhiyuan
中科院分区：
文献类型：
--
作者：
Yang, Can;Zhang, Zijing;Wu, Zhiyuan
肿瘤微环境（TME）的免疫背景对于有效的免疫治疗至关重要。尽管如此，免疫敏感性TME的基于DNA的生物标志物和免疫检查点抑制剂（ICI）应答者的鉴定仍处于探索阶段。这项研究旨在全面地了解同源重组缺陷（HRD）评分，这是肿瘤基因组不稳定性的一个新标志，它触发了主要癌症类型的免疫反应，并揭示了它们与TME和免疫应答的联系。在来自TCGA的32种癌症类型的9088个肿瘤样本中表征了HRD相关的基因组瘢痕。我们使用独立的乳腺癌队列（GSE 87049）和11个接受抗PD 1/CTLA 4方案治疗的体内鼠乳腺肿瘤模型（GSE 124821）评估了HRD评分在对ICI反应者进行分类方面的性能。这项研究揭示了HRD高基因型与主要癌症类型中的新抗原发生之间的广泛关联，包括膀胱癌、乳腺癌、头颈部鳞状细胞癌、肺腺癌、肺鳞状细胞癌、卵巢癌和肉瘤。具有高HRD评分的肿瘤具有增加的白细胞浸润和淋巴细胞分数，并表现出免疫敏感的微环境。肿瘤免疫功能障碍和排斥（TIDE）模型进一步证实了HRD评分高的基因型作为乳腺癌ICI免疫治疗应答者的潜在预测因子。总之，具有高HRD评分的肿瘤表现出免疫敏感性TME。HRD高基因型是一个有前途的标记，用于识别乳腺癌患者中ICI治疗反应。
The immune context of the tumor microenvironment (TME) is critical for effective immunotherapy. Nonetheless, DNA-based biomarkers for the immune-sensitive TME and the identification of immune checkpoint inhibitor (ICI) responders are under-explored. This study aims to comprehensively landscape the homologous recombination deficiency (HRD) score, an emerging hallmark for tumor genome instability that triggers immune responsiveness across major cancer types, and to unveil their link to the TME and immunotherapeutic response. The HRD-associated genomic scars were characterized in 9088 tumor samples across 32 cancer types from TCGA. We evaluated the HRD score's performance in classifying ICI responders using an independent breast cancer cohort (GSE87049) and 11 in vivo murine mammary tumor models treated with anti-PD1/CTLA4 regimen (GSE124821). This study revealed a broad association between HRD-high genotype and neoantigenesis in the major cancer types including bladder cancer, breast cancer, head and neck squamous carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian cancer, and sarcoma. Tumors with high HRD score bears increased leukocyte infiltration and lymphocyte fraction and demonstrated immune-sensitive microenvironment. The tumor immune dysfunction and exclusion (TIDE) model further confirmed HRD score-high genotype as a potential predictor for ICI immunotherapy responders in breast cancer. In conclusion, tumors with high HRD score exhibit an immune-sensitive TME. The HRD-high genotype is a promising marker for identifying ICI therapy responders among breast cancer patients.