Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer.

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.

Identification of Differential Tumor Subtypes of T1 Bladder Cancer.

Stage T1 bladder cancers have the highest progression and recurrence rates of all non-muscle-invasive bladder cancers (NMIBCs). Most T1 cancers are treated with bacillus Calmette-Guérin (BCG), but many will progress or recur, and some T1 patients will die from bladder cancer. Particularly aggressive tumors could be treated with early cystectomy. To better understand the molecular heterogeneity of T1 cancers, we performed transcriptome profiling and unsupervised clustering, and identified five consensus subtypes of T1 tumors treated with repeat transurethral resection (reTUR) and induction and maintenance BCG. The T1-LumGU subtype was associated with carcinoma in situ (CIS; six/13, 46% of all CIS), had high E2F1 and EZH2 expression, and was enriched in E2F target and G2M checkpoint hallmarks. The T1-Inflam subtype was inflamed and infiltrated with immune cells. While most T1 tumors were classified as luminal papillary, the T1-TLum subtype had the highest median luminal papillary score and FGFR3 expression, no recurrence events, and the fewest copy number gains. T1-Myc and T1-Early subtypes had the most recurrences (14/30 within 24 mo), the highest median MYC expression, and, when combined, had significantly worse recurrence-free survival than the other three subtypes. T1-Early had five (38%) recurrences within the first 6 mo of BCG, and repressed IFN-α and IFN-γ hallmarks and inflammation. We developed a single-patient T1 classifier and validated our subtype biology in a second cohort of T1 tumors. Future research will be necessary to validate the proposed T1 subtypes and to determine if therapies can be individualized for each subtype. PATIENT SUMMARY: We identified and characterized expression subtypes of high-grade stage T1 bladder cancer that are biologically heterogeneous and have variable responses to bacillus Calmette-Guérin treatment. We validated the subtypes and describe a single-patient classifier.

Field pathogenomics of Fusarium head blight reveals pathogen transcriptome differences due to host resistance.

Fusarium head blight (FHB), caused by Fusarium graminearum and other Fusarium species, is a detrimental disease that affects small grains such as wheat around the world. Management of FHB is difficult, and surveillance as well as a better understanding of pathogen aggressiveness is needed for improved control. F. graminearum disease severity varies depending on the resistance of the host genotype. In this study, we used the field pathogenomics method to investigate gene expression and population structure of isolates collected from wheat lines of varying resistance levels (susceptible, intermediate, and resistant) as well as an axenic control. Differential gene expression was found among isolates collected from different host genotypes. Candidate gene sets were identified for both F. graminearum infection of specific host genotypes and general infection to wheat. Population structure of isolates from different resistance level sources was the same, with all isolates belonging to the NA1 population.