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- Title
Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer.
- Authors
Robertson, A. Gordon; Meghani, Khyati; Cooley, Lauren Folgosa; McLaughlin, Kimberly A.; Fall, Leigh Ann; Yu, Yanni; Castro, Mauro A. A.; Groeneveld, Clarice S.; de Reyniès, Aurélien; Nazarov, Vadim I.; Tsvetkov, Vasily O.; Choy, Bonnie; Raggi, Daniele; Marandino, Laura; Montorsi, Francesco; Powles, Thomas; Necchi, Andrea; Meeks, Joshua J.
- Abstract
Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced-stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling. We identify five distinctive genetic and transcriptomic programs and validate these in an independent neoadjuvant CPI trial to identify the features of response or resistance to CPI. By modeling the regulatory network, we identify the histone demethylase KDM5B as a repressor of tumor immune signaling pathways in one resistant subtype (S1, Luminal-excluded) and demonstrate that inhibition of KDM5B enhances immunogenicity in FGFR3-mutated BCa cells. Our study identifies signatures associated with response to CPI that can be used to molecularly stratify patients and suggests therapeutic alternatives for subtypes with poor response to neoadjuvant immunotherapy. The response to checkpoint immunotherapy within bladder cancer patients is highly variable. Here, the authors use RNA-seq, ATAC-seq and digital spatial profiling of pre- and post-treatment samples from the PURE01 trial to identify subtypes associated with treatment response.
- Subjects
IMMUNE checkpoint inhibitors; CANCER invasiveness; BLADDER cancer; IMMUNE response; TUMOR microenvironment; IMMUNOCOMPUTERS; BREAST
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-37568-9