Dr Bellmunt on Predictive Signatures for Checkpoint Inhibitor Responses in Urothelial Cancer

Joaquim Bellmunt, MD, PhD, associate professor, medicine, Harvard Medical School; director, Bladder Cancer Center, Genitourinary Oncology Program, Dana-Farber Cancer Institute, discusses research on the predictive value of combined high-resolution H3K27ac epigenomic and single-cell transcriptional profiling of neoadjuvant immune checkpoint inhibitors in urothelial cancer.

In metastatic urothelial carcinoma, several molecular predictors such as clonal tumor mutational burden, APOBEC mutagenesis, and various RNA signatures have been associated with responses to immune checkpoint inhibitors, Bellmunt begins. However, other factors predictive of responses or driving resistance to PD-1/PD-L1 inhibitors in muscle-invasive bladder cancer (MIBC) remain inadequately characterized. To address this, investigators launched a study using epigenomic analysis combined with single-cell technology to uncover mechanisms of response involving both cancer cells and the tumor microenvironment in patients with urothelial cancer.

Two cohorts of patients with MIBC from Dana-Farber Cancer Institute and Hospital Trias i Pujol in Spain were identified. These patients were treated with neoadjuvant immunotherapy and had tissue samples available pre- and post-treatment.

Chromatin immunoprecipitation sequencing was performed using the H3K27ac acetylation marker to identify areas of open chromatin, indicative of active enhancers and promoters. The correlation between these markers and patient response to immunotherapy was analyzed. The H3K27ac enhancer analysis revealed a signature predictive of treatment response to immunotherapy, Bellmunt reports. Enhancers more active in pre-treatment samples from responders were found to be highly represented in lymphoid lineages, while those less active in responders were associated with squamous differentiation.

When translated into a gene expression signature, novel and known genes in urothelial cancer were identified, including CYTOR, TGFBR2, and IKZF1, which are involved in immunotherapy response. Additional genes included FYN, PDE4B, and GPR174, which are associated with cell migration, the microenvironment, and epithelial-mesenchymal transition.

This predictive signature was developed from a limited number of patients receiving neoadjuvant immunotherapy in the muscle-invasive setting, with tissue samples analyzed both before and after treatment. These findings now need to be confirmed in external cohorts to validate the potential of this signature as a predictive biomarker for immunotherapy response in MIBC, Bellmunt concludes.