Identification of ferroptosis-related signature with potential implications in prognosis and immunotherapy of renal cell carcinoma
Identification of ferroptosis-related signature with potential implications in prognosis and immunotherapy of renal cell carcinoma
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DOI：
10.1007/s10495-022-01766-5
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发表时间：
2022-08
期刊：
影响因子：
7.2
通讯作者：
Lingfeng Liu;Huan Jin;Mengyuan Dong;Jingwen Tian;Hongsheng Li;Quentin Liu;Yibing Chen;Zhengzhi Zou
中科院分区：
文献类型：
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作者：
Lingfeng Liu;Huan Jin;Mengyuan Dong;Jingwen Tian;Hongsheng Li;Quentin Liu;Yibing Chen;Zhengzhi Zou
针对不同肾癌患者的个体化治疗是提高免疫治疗疗效的关键。已有报道称，铁凋亡参与T细胞介导的抗肿瘤免疫，靶向肿瘤铁凋亡途径的治疗方法联合免疫检查点阻断药物提高了癌症免疫治疗的疗效。本研究特别关注铁凋亡基因，以确定反映不同肾细胞癌亚型预后的新生物标志物。采用LASSO算法和多变量考克斯回归方法识别铁中毒相关多基因风险信号（FRGsig），建立FRGsig评分模型。我们使用多种肿瘤微环境基因特征和方法来推断肿瘤微环境状态和免疫细胞侵袭水平。我们的研究发现，高FRGsig评分与肾细胞癌主要组织学亚型患者的不良预后相关。FRGsig评分高的样本有较高水平的抗肿瘤免疫细胞浸润，存在抗肿瘤炎症促进免疫抑制细胞募集或分化的反馈机制。FRGsig是预测肾透明细胞癌和肾乳头状细胞癌对免疫检查点阻断治疗反应的潜在生物标志物，FRGsig高的肾乳头状细胞癌患者对抗VEGF治疗的反应更好。我们的研究结果为评估肾细胞癌主要组织学亚型的免疫治疗敏感性提供了进一步的见解。FRGsig可能是一种潜在的生物标志物，用于预测血管生成阻断药物或免疫检查点抑制剂在不同肾细胞癌亚型中的疗效，从而实现更精确的患者选择。
Developing individualized therapies for different renal cell carcinoma patients is pivotal for improving the efficacy of immunotherapy. It has been reported that ferroptosis is involved in T cell-mediated anti-tumor immunity, and that therapeutic approaches targeting tumor ferroptosis pathway in combination with immune checkpoint blockade drugs improve the efficacy of cancer immunotherapy. This study focused specifically on ferroptosis genes to identify novel biomarkers that reflect prognosis in different renal cell carcinoma subtypes. LASSO algorithm and multivariate Cox regression were initiated for identifying ferroptosis-related multigene risk signature (FRGsig) and established a FRGsig score model. We used multiple tumor microenvironment gene signatures and methods to infer tumor microenvironment status and immune cell invasion levels. Our study found that high FRGsig score was associated with poor prognosis in patients with predominant histologic subtypes of renal cell carcinoma. And high FRGsig score samples had higher levels of anti-tumor immunity cells infiltration, and there was a feedback mechanism whereby anti-tumor inflammation promoted the recruitment or differentiation of immunosuppressive cells. FRGsig was a potential biomarker for predicting the response to immune checkpoint blockade therapy in kidney clear cell carcinoma and kidney papillary cell carcinoma, and the kidney papillary cell carcinoma patients with high FRGsig was associated with better response to anti-VEGF therapy. Our findings provided further insights into assessing immunotherapy sensitivity of predominant histologic subtypes of renal cell carcinoma. FRGsig might be a potential biomarker for predicting the efficacy of angiogenic blocking drugs or immune checkpoint inhibitors in different renal cell carcinoma subtypes, enabling more precise patient selection.