Background
Urothelial bladder cancer (UBC) is one of the most lethal cancers worldwide, the 5-year survival rate remain poor with platinum-based chemotherapy regimens as the standard of cancer treatment protocol. Recent FDA approval of a programmed death ligand-1 (PD-L1) inhibitor, atezolizumab, in advanced UBC patients is changing the therapeutic landscape. Although the response to anti-PD-L1 is correlated to PD-L1 expression and tumor mutation burden, the molecule determinants of responsiveness or non-responsiveness to immune checkpoint inhibitor (ICI) is largely unknown.
Result
A published immunotherapy cohort with whole exome sequencing, RNAseq and clinic outcome data for 29 metastatic urothelial cancer patients was used, paralleled with The Cancer Genome Altas Bladder Cancer cohort for validation. Genomic mutational profiling, mutational signature, a panel genes in antigen presentation and interferon signaling in bladder cancer were delineated with little correlation with durable clinic benefit (DCB) or non-DCB of PD-L1 inhibitor treatment. Whereas, characterized immune-responsive or resistant associated genes showed differentially expressed between DCB group and non-DCB group. Further more, transcriptional signature and transcriptional regulators between DCB and non-DCB were identified from transcripome data.
Conclusion
Our exploratory analyses provided multidimension view of complexity of determinants of immune-responsiveness and suggest the influences of transcriptional reprogram in immune checkpoint blockage therapy.