Genomic Profiling and Immune Phenotyping of Neuroendocrine Bladder Cancer.

Abstract

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.