Abstract: We combined single nuclei RNA sequencing with spatial transcriptomics and single-cell resolution spatial proteomic analysis of human bladder cancer to identify an epithelial subpopulation with therapeutic response prediction ability. These cells express Cadherin 12 (CDH12, N-Cadherin 2), catenins, and other epithelial markers. CDH12-enriched tumors define patients with poor outcome following surgery with or without neoadjuvant chemotherapy (NAC), whereas CDH12-enriched tumors have a superior response to immune checkpoint therapy (ICT). Patient stratification by tumor CDH12 enrichment offered better prediction outcome than established bladder cancer subtypes. The CDH12 population resembles an undifferentiated state with chemoresistance. CDH12-enriched cells express PD-L1 and PD-L2 and co-localize with exhausted T-cells, possibly mediated through CD49a (ITGA1), likely explaining ICT efficacy in these tumors.

Abstract: The present invention provides a method for targeted cell retrieval, comprising: providing a population of barcoded cells, said population comprising a plurality of different barcodes, each of the plurality of different barcodes being uniquely targetable with a target-specific CRISPR RNA; introducing a CRISPR-Cas system, or one or more vectors encoding the components of the CRISPR-Cas system, into the population of barcoded cells said CRISPR-Cas system having a target-specific CRISPR RNA that targets a first barcode of said plurality of different barcodes, thereby causing a CRISPR-Cas system-mediated change at a target site leading to a change in one or more detectable properties of at least one cell carrying said first barcode; and retrieving said at least one cell carrying said first barcode based on the change in said one or more detectable properties. Also provided are products and kits for use in the method of the invention.