State Key Laboratory of Systems Medicine for Cancer, Department of Radiation Oncology, Department of Urology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Clin Cancer Res. 2024 Nov 1;30(21):4920-4931. doi: 10.1158/1078-0432.CCR-24-1277.
Neuroendocrine bladder cancer (NEBC) poses a formidable clinical challenge and attracts keen interests to explore immunotherapy as a viable treatment option. However, a comprehensive immunogenomic landscape has yet to be thoroughly investigated.
Leveraging a long-term cohort of natural NEBC cases, we employed a multimodal approach integrating genomic (n = 19), transcriptomic (n = 3), single-cell RNA sequencing (n = 1), and IHC analyses (n = 34) to meticulously characterize the immunogenicity and immunotypes of primary NEBC tumors. Information on clinical, pathologic, medical imaging, and treatment aspects was retrospectively retrieved and analyzed.
Our study unveiled that despite a considerable mutational burden, NEBC was typically immunologically inactive, as manifested by the "immune-excluded" or "immune-desert" microenvironment. Interestingly, a subset of mixed NEBC with concurrent urothelial bladder cancer histology displayed an "immune-infiltrated" phenotype with prognostic relevance. When compared with urothelial bladder cancer, NEBC lesions were distinguished by a denser cellular composition and augmented peritumoral extracellular matrix, which might collectively impede lymphatic infiltration. As a result, single-agent immune checkpoint inhibitors demonstrated limited efficacy against NEBC, whereas pharmacologic immunostimulation with combination chemotherapy conferred a more favorable response.
These new insights derived from genomic profiling and immune phenotyping pave the way for rational immunotherapeutic interventions in patients with NEBC, with the potential to ultimately reduce mortality from this otherwise fatal disease.
神经内分泌膀胱癌（NEBC）是一个严峻的临床挑战，激发了人们探索免疫疗法作为一种可行治疗选择的强烈兴趣。然而，全面的免疫基因组景观仍有待深入研究。
利用长期自然发生的 NEBC 病例队列，我们采用了一种多模式方法，整合了基因组（n=19）、转录组（n=3）、单细胞 RNA 测序（n=1）和 IHC 分析（n=34），以细致地描绘原发性 NEBC 肿瘤的免疫原性和免疫类型。回顾性检索和分析了临床、病理、医学影像学和治疗方面的信息。
我们的研究表明，尽管存在相当大的突变负担，NEBC 通常是免疫无活性的，表现为“免疫排斥”或“免疫荒漠”微环境。有趣的是，一部分具有混合性 NEBC 并伴有同时性尿路上皮膀胱癌组织学特征的肿瘤显示出具有预后相关性的“免疫浸润”表型。与尿路上皮膀胱癌相比，NEBC 病变的特点是细胞成分更密集，肿瘤周围细胞外基质增加，这可能共同阻碍淋巴浸润。因此，单一免疫检查点抑制剂对 NEBC 的疗效有限，而联合化疗的药物免疫刺激则具有更有利的反应。
这些源自基因组分析和免疫表型分析的新见解为 NEBC 患者的合理免疫治疗干预铺平了道路，有可能最终降低这种致命疾病的死亡率。
