Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer.
A Gordon RobertsonKhyati MeghaniLauren Folgosa CooleyKimberly A McLaughlinLeigh Ann FallYanni YuMauro Antonio Alves CastroClarice S GroeneveldAurélien de ReynièsVadim I NazarovVasily O TsvetkovBonnie ChoyDaniele RaggiLaura MarandinoFrancesco MontorsiThomas PowlesAndrea NecchiJoshua J MeeksPublished in: Nature communications (2023)
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.
Keyphrases
- rectal cancer
- locally advanced
- end stage renal disease
- lymph node
- ejection fraction
- chronic kidney disease
- signaling pathway
- induced apoptosis
- prognostic factors
- single cell
- dna methylation
- public health
- peritoneal dialysis
- poor prognosis
- gene expression
- neoadjuvant chemotherapy
- endoplasmic reticulum stress
- phase iii
- cell proliferation
- cell cycle
- tyrosine kinase