Spatial remodeling of the urothelial carcinoma tumor microenvironment shapes response to neoadjuvant atezolizumab

The ABACUS study was a single arm, phase II trial evaluating neoadjuvant atezolizumab in operable urothelial carcinoma. Initial bulk transcriptomic and immunohistochemistry analyses suggested links between immune activation, tissue remodeling, and resistance pathways such as transforming growth factor {beta} that were associated with clinical outcome. To further characterize spatial and phenotypic changes at high resolution, artificial intelligence-assisted digital image analysis of hematoxylin and eosin sections and spatial transcriptomics were performed on paired tissue samples. In baseline samples, cells residing in lymphoid aggregates and tertiary lymphoid structures were more abundant in stable disease than in relapse and exhibited gene expression programs associated with improved survival in urothelial carcinoma. Most spatial features reflected shared pharmacodynamic changes between stable disease and relapse; however, carcinoma-endothelial adjacency was reduced significantly following treatment and differed between groups, accompanied by distinct transcriptional programs. Together, these findings indicate that atezolizumab induces localized immune and stromal remodeling within the tumor microenvironment, while non-response despite immune expansion is associated with persistent spatial immune exclusion and carcinoma-endothelial adjacency. Spatial and phenotypic biomarkers identified here may inform rational combination strategies for immune checkpoint inhibitor-refractory urothelial carcinoma.