Genomic Profiling and Immune Phenotyping of Neuroendocrine Bladder Cancer.

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. ©2024 American Association for Cancer Research.

Citation

Jingyu Zang, Akezhouli Shahatiaili, Mei-Chun Cai, Di Jin, Peiye Shen, Lei Qian, Lu Zhang, Tianxiang Zhang, Yuchen Wu, Fan Yang, Zheng Wu, Yanli Hou, Yongrui Bai, Jun Xia, Liang Cheng, Ruiyun Zhang, Guanglei Zhuang, Haige Chen. Genomic Profiling and Immune Phenotyping of Neuroendocrine Bladder Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Nov 01;30(21):4920-4931

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PMID: 39226396

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