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开发和实验验证与 B 细胞耗竭相关的基因特征，以评估膀胱癌的预后和免疫治疗反应。

Developing and experimental validating a B cell exhaustion-related gene signature to assess prognosis and immunotherapeutic response in bladder cancer.

机构信息

Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou 510080, Guangdong, China; The First Clinical Medical College, Southern Medical University, Guangzhou 510080, Guangdong, China.

出版信息

Gene. 2024 Nov 15;927:148634. doi: 10.1016/j.gene.2024.148634. Epub 2024 Jun 5.

DOI:10.1016/j.gene.2024.148634

PMID:38848880

Abstract

BACKGROUND

B cell exhaustion (BEX) refers to the impairment of normal B cell functions and decreased proliferation capability. However, the prognostic value of BEX-related genes in bladder cancer (BLCA) remains unclear.

METHODS

BLCA cases from TCGA were used for training, while GSE5287, GSE13507, GSE31684, and GSE32894 cohorts from GEO were used for external validation. BEX-related genes were identified through literature retrieval, unsupervised clustering, and genomic difference detection. Gene pairing, LASSO, random forest, and Cox regression were employed to construct a predictive model. B cell samples from scRNAseqDB, GSE111636, and IMvigor210 were utilized to explore immunoprofiles and the predictive ability of the model in immunotherapeutic response. Additionally, 21 pairs of BLCA and paracarcinoma samples from Nanfang Hospital were used to re-confirm our findings through RT-qPCR, immunofluorescence, and flow cytometry.

RESULTS

39 BEX-related genes were identified. A 4-gene-pair signature was constructed and served as a reliable prognostic predictor across multiple datasets (pooled HR = 2.32; 95 % CI = 1.81-2.98). The signature reflected the BEX statuses of B cells (FDR < 0.05) and showed promise in evaluating immunotherapeutic sensitivity (P < 0.001). In the local cohort, CD52, TUBB6, and CAV1 were down-regulated in BLCA tissues, while TGFBI, UBE2L6, TINAGL1, and IL32 were up-regulated (all P < 0.05). Furthermore, the infiltration levels of CD19 + CD52 + and CD19 + TUBB6 + B cells in paracarcinoma samples were higher than those in BLCA samples (all P < 0.05).

CONCLUSION

A BEX-related gene signature was developed to predict prognosis and immunotherapeutic sensitivity in BLCA, providing valuable guidance for personalized treatment.

摘要

背景

B 细胞耗竭（BEX）是指正常 B 细胞功能受损和增殖能力下降。然而，BEX 相关基因在膀胱癌（BLCA）中的预后价值尚不清楚。

方法

TCGA 的 BLCA 病例用于训练，而 GEO 的 GSE5287、GSE13507、GSE31684 和 GSE32894 队列用于外部验证。通过文献检索、无监督聚类和基因组差异检测确定 BEX 相关基因。基因配对、LASSO、随机森林和 Cox 回归用于构建预测模型。利用 scRNAseqDB、GSE111636 和 IMvigor210 中的 B 细胞样本探索免疫特征和模型在免疫治疗反应中的预测能力。此外，从南方医院收集了 21 对 BLCA 和癌旁组织样本，通过 RT-qPCR、免疫荧光和流式细胞术重新验证了我们的发现。

结果

鉴定出 39 个 BEX 相关基因。构建了一个由 4 个基因对组成的特征，该特征在多个数据集（合并 HR=2.32；95%CI=1.81-2.98）中均为可靠的预后预测因子。该特征反映了 B 细胞的 BEX 状态（FDR<0.05），并在评估免疫治疗敏感性方面具有潜力（P<0.001）。在本地队列中，BLCA 组织中 CD52、TUBB6 和 CAV1 下调，而 TGFBI、UBE2L6、TINAGL1 和 IL32 上调（均 P<0.05）。此外，癌旁组织样本中 CD19+CD52+和 CD19+TUBB6+B 细胞的浸润水平高于 BLCA 样本（均 P<0.05）。