Wang Song, Wang He, Zhu Shaoxing, Li Fangyin
Department of Urology, Cancer Hospital of University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.
The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China.
Front Oncol. 2022 Oct 24;12:1040892. doi: 10.3389/fonc.2022.1040892. eCollection 2022.
Bladder cancer (BCa) is a life-threaten disease with an increasing incidence with age, and immunotherapy has become an important treatment for BCa, while the efficiency of the immune system declines with age. It is vital to reveal the mechanisms of tumor immune microenvironment (TIME) and identify novel immunotherapy targets for BCa. Through analyzing the RNA-seq of TCGA-BLCA cohort, we distinguished two ferroptosis-related BCa clusters, and we discovered that in comparation with cluster 2, the cluster 1 BCa patients showed higher PD-L1 expression, more unfavorable overall survival and higher tumor stage and grade. XCELL analyses showed that higher level of Th2 cell and Myeloid dendritic cell were enriched in cluster 1, while NK T cell was enriched in cluster 2, and TIDE analysis revealed that cluster 2 was more sensitive to immunotherapy than cluster 1. GSEA analysis implied that Toll-like signaling pathway and JAK_STAT signaling pathway were significantly enriched in cluster 1. Subsequently, through performing bioinformatic analysis and cell experiments, we demonstrated that GCLM is overexpressed in BCa and indicates dismal prognosis, and knockdown of GCLM can significantly suppress the colony formation ability of BCa cells. Furthermore, we also found that GCLM might be correlated with immune infiltration in BCa, and can serve as a tumor promotor and immunological biomarker in BCa, our research showed the vital roles of ferroptosis regulators in TIME of BCa, and GCLM is a latent therapeutic target for cancer immunotherapy.
膀胱癌（BCa）是一种威胁生命的疾病，其发病率随年龄增长而上升，免疫疗法已成为BCa的重要治疗方法，而免疫系统的效率会随着年龄的增长而下降。揭示肿瘤免疫微环境（TIME）的机制并确定BCa的新型免疫治疗靶点至关重要。通过分析TCGA-BLCA队列的RNA测序，我们区分了两个与铁死亡相关的BCa簇，并且我们发现与簇2相比，簇1的BCa患者表现出更高的PD-L1表达、更差的总生存率以及更高的肿瘤分期和分级。XCELL分析表明，簇1中Th2细胞和髓样树突状细胞的水平较高，而簇2中富集NK T细胞，并且TIDE分析显示簇2比簇1对免疫疗法更敏感。GSEA分析表明，Toll样信号通路和JAK_STAT信号通路在簇1中显著富集。随后，通过进行生物信息学分析和细胞实验，我们证明GCLM在BCa中过表达并预示预后不良，敲低GCLM可显著抑制BCa细胞的集落形成能力。此外，我们还发现GCLM可能与BCa中的免疫浸润相关，并且可作为BCa中的肿瘤促进因子和免疫生物标志物，我们的研究表明铁死亡调节因子在BCa的TIME中起着重要作用，并且GCLM是癌症免疫治疗的潜在治疗靶点。
