Prognostic value, DNA variation and immunologic features of a tertiary lymphoid structure-related chemokine signature in clear cell renal cell carcinoma
Prognostic value, DNA variation and immunologic features of a tertiary lymphoid structure-related chemokine signature in clear cell renal cell carcinoma
复制标题
透明细胞肾细胞癌三级淋巴结构相关趋化因子特征的预后价值、DNA 变异和免疫学特征
DOI：
10.1007/s00262-021-03123-y
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发表时间：
2022-01-19
影响因子：
5.8
通讯作者：
Ye, Dingwei
中科院分区：
文献类型：
--
作者：
Xu, Wenhao;Ma, Chunguang;Ye, Dingwei
背景肿瘤微环境（TME）和三级淋巴样结构（TLS）影响肿瘤的发生和发展。免疫环境如何与肾透明细胞癌（ccRCC）的表型相互作用仍不清楚。方法我们使用机器学习算法和TLS的12-趋化因子基因签名识别和评估ccRCC中的TLS簇。分析了ccRCC中CXCL 13的功能富集、DNA变异、免疫细胞分布、与独立临床病理特征的相关性以及预测价值。结果我们发现与其他类型的肾细胞癌相比，在ccRCC患者中TLS的12-趋化因子基因签名显著富集。我们确定了ccRCC中CCL 4、CCL 5、CCL 8、CCL 19和CXCL 13表达的预后价值。与扩增和野生型基因签名相比，TLS基因签名的DNA缺失显著预测ccRCC的不良结局。我们建立了TLS集群（C1-4），并观察到集群之间的生存率，干细胞样特征，免疫细胞分布，对免疫疗法和VEGF靶向疗法的反应存在明显差异。我们发现，在一个真实世界验证队列中，CXCL 13表达升高显著预测了232例ccRCC患者的侵袭性进展和不良预后。结论本研究描述了一个由12个趋化因子组成的ccRCC TLS基因标签，建立了反映不同TME免疫状态的TLS基因簇，并与ccRCC的预后相对应。我们证实了在ccRCC中TIL聚集和TLS的密集存在，并证明了ccRCC的CXCL 13表达的致癌作用，这有助于开发免疫疗法并为ccRCC的长期管理提供新的见解。
Background The tumor microenvironment (TME) and tertiary lymphoid structures (TLS) affect the occurrence and development of cancers. How the immune contexture interacts with the phenotype of clear cell renal cell carcinoma (ccRCC) remains unclear. Methods We identified and evaluated TLS clusters in ccRCC using machine learning algorithms and the 12-chemokine gene signature for TLS. Analyses for functional enrichment, DNA variation, immune cell distribution, association with independent clinicopathological features and predictive value of CXCL13 in ccRCC were performed. Results We found a prominently enrichment of the 12-chemokine gene signature for TLS in patients with ccRCC compared with other types of renal cell carcinoma. We identified a prognostic value of CCL4, CCL5, CCL8, CCL19 and CXCL13 expression in ccRCC. DNA deletion of the TLS gene signature significantly predicted poor outcome in ccRCC compared with amplification and wild-type gene signature. We established TLS clusters (C1-4) and observed distinct differences in survival, stem cell-like characteristics, immune cell distribution, response to immunotherapies and VEGF-targeted therapies among the clusters. We found that elevated CXCL13 expression significantly predicted aggressive progression and poor prognosis in 232 patients with ccRCC in a real-world validation cohort. Conclusion This study described a 12-chemokine gene signature for TLS in ccRCC and established TLS clusters that reflected different TME immune status and corresponded to prognosis of ccRCC. We confirmed the dense presence of TILs aggregation and TLS in ccRCC and demonstrated an oncogenic role of CXCL13 expression of ccRCC, which help develop immunotherapies and provide novel insights on the long-term management of ccRCC.