Wahafu Wasilijiang, Zhou Quan, Yang Xihua, Yang Yongming, Zhao Yuanyuan, Wang Zhu, Kang Xiangpeng, Ye Xiongjun, Xing Nianzeng
Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
Department of Urology, Shanxi Province Cancer Hospital/Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences/Cancer Hospital Affiliated to Shanxi Medical University, Taiyuan, Shanxi, 030013, China.
J Transl Med. 2025 Mar 27;23(1):375. doi: 10.1186/s12967-025-06358-w.
The identification of the complex spatial architecture of immune cell infiltration and its interaction mechanisms within tumor ecosystems provides crucial insights into therapeutic responses to neoadjuvant therapy in muscle-invasive bladder cancer (MIBC). This study aims to characterize the spatial features of distinct cell-type niches within the tumor microenvironment (TME) of patients with varying responses to neoadjuvant therapy.
We performed spatial transcriptomic profiling on six MIBC specimens obtained from a registered clinical trial (ChiCTR2000032359), generating whole-transcriptome spatial atlases to map the TME architecture. High-throughput analytical frameworks were employed to deconstruct the TME, and key findings were validated through immunohistochemistry and mouse model experiments.
Our analysis revealed that tissues from complete responders exhibited greater infiltration of T and B cells, with the formation of tertiary lymphoid structure (TLS). Trajectory analysis identified CCL19/CCL21 as the key signaling molecules driving TLS formation in MIBC. Mouse experiments demonstrated that recombinant CCL19/CCL21 protein injections promoted intratumoral TLS formation and enhance the efficacy of immunotherapy. Furthermore, we observed significant intrinsic heterogeneity within individual tumors, which may contribute to the lack of therapeutic efficacy in MIBC.
This study underscores the critical role of TLS formation in the response to neoadjuvant therapy in MIBC. We identified CCL19/CCL21 as key drivers of TLS formation within MIBC tumors and potential immune-sensitizing agents. Additionally, the intrinsic heterogeneity of tumor should be considered a significant factor influencing therapeutic efficacy.
识别免疫细胞浸润的复杂空间结构及其在肿瘤生态系统中的相互作用机制，对于深入了解肌肉浸润性膀胱癌（MIBC）新辅助治疗的疗效至关重要。本研究旨在描述对新辅助治疗有不同反应的患者肿瘤微环境（TME）中不同细胞类型微环境的空间特征。
我们对从一项注册临床试验（ChiCTR2000032359）获得的6个MIBC标本进行了空间转录组分析，生成全转录组空间图谱以绘制TME结构。采用高通量分析框架解构TME，并通过免疫组织化学和小鼠模型实验验证关键发现。
我们的分析表明，完全缓解者的组织中T细胞和B细胞浸润更多，形成了三级淋巴结构（TLS）。轨迹分析确定CCL19/CCL21是驱动MIBC中TLS形成的关键信号分子。小鼠实验表明，注射重组CCL19/CCL21蛋白可促进肿瘤内TLS形成并增强免疫治疗效果。此外，我们观察到单个肿瘤内存在显著的内在异质性，这可能是MIBC治疗效果不佳的原因之一。
本研究强调了TLS形成在MIBC新辅助治疗反应中的关键作用。我们确定CCL19/CCL21是MIBC肿瘤内TLS形成的关键驱动因素和潜在的免疫致敏剂。此外，肿瘤的内在异质性应被视为影响治疗效果的重要因素。
