Department of Urology, the Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, 450000, Henan Province, China.
Sci Rep. 2023 Nov 10;13(1):19563. doi: 10.1038/s41598-023-44028-3.
Bladder cancer (BCa) is heterogeneous in the tumour microenvironment (TME). However, the role of the TME in BCa in modulating the response to immunotherapy has not been fully explored. We therefore analysed fractions of immune cells using CIBERSORTx and clustered BCa into subtypes. We also analyzed weighted correlation networks to generate immunotherapy-related hub genes that we used to construct a prediction model using multivariate Cox and LASSO regression analyses. We found that BCa comprised three subtypes (C1‒C3). The prognosis of the patients was the most favourable and the response rate to anti-programmed death ligand 1 (PD-L1) was the highest in C1 among the three subtypes. Immune cells, including CD8, CD4 memory activated, and follicular helper T cells, activated NK cells, and M1 macrophages infiltrated the C1 subtype. The C2 subtype was enriched in M0 macrophages and activated mast cells, and the C3 subtype was enriched in B and resting immune cells. Mechanistically, the enhanced immunogenicity of subtypes C1 and C2 correlated positively with a higher response rate, whereas the dysregulated ECM-related pathways in the C2 subtype and glycolytic and fatty acid metabolic pathways in the C3 subtype impaired the responses of patients to anti-PD-L1 therapy. We also constructed a TME-related signature based on 18 genes that performed well in terms of overall survival. In conclusion, we determined prognoses and anti-PD-L1 responses by analysing TME heterogeneity in BCa.
膀胱癌(BCa)在肿瘤微环境(TME)中具有异质性。然而,TME 在调节免疫治疗反应中的作用尚未得到充分探索。因此,我们使用 CIBERSORTx 分析了免疫细胞的分数,并将 BCa 聚类为亚型。我们还分析了加权相关网络,以生成与免疫治疗相关的枢纽基因,我们使用多元 Cox 和 LASSO 回归分析构建了一个预测模型。我们发现 BCa 包含三个亚型(C1-C3)。在这三个亚型中,C1 型患者的预后最好,对抗程序性死亡配体 1(PD-L1)的反应率最高。包括 CD8、CD4 记忆激活和滤泡辅助 T 细胞、激活 NK 细胞和 M1 巨噬细胞在内的免疫细胞浸润了 C1 亚型。C2 亚型富含 M0 巨噬细胞和激活的肥大细胞,C3 亚型富含 B 细胞和静止免疫细胞。从机制上讲,C1 和 C2 亚型增强的免疫原性与更高的反应率呈正相关,而 C2 亚型中失调的 ECM 相关途径和 C3 亚型中糖酵解和脂肪酸代谢途径损害了患者对抗 PD-L1 治疗的反应。我们还构建了一个基于 18 个基因的 TME 相关特征,这些基因在总体生存方面表现良好。总之,我们通过分析 BCa 中的 TME 异质性来确定预后和抗 PD-L1 反应。
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