Multi-Omics Analysis of Novel Signature for Immunotherapy Response and Tumor Microenvironment Regulation Patterns in Urothelial Cancer

The tumor microenvironment (TME) is mainly composed of tumor cells, tumor-infiltrating immune cells, and stromal components. It plays an essential role in the prognosis and therapeutic response of patients. Nonetheless, the TME landscape of urothelial cancer (UC) has not been fully elucidated. In this study, we systematically analyzed several UC cohorts, and three types of TME patterns (stromal-activation subtype, immune-enriched subtype and immune-suppressive subtype) were defined. The tumor microenvironment signature (TMSig) was constructed by modified Lasso penalized regression. Patients were stratified into high- and low-TMSig score groups. The low-score group had a better prognosis (p < 0.0001), higher M1 macrophage infiltration (p < 0.01), better response to immunotherapy (p < 0.05), and more similar molecular characteristics to the luminal (differentiated) subtype. The accuracy of the TMSig for predicting the immunotherapy response was also verified in three independent cohorts. We highlighted that the TMSig is an effective predictor of patient prognosis and immunotherapy response. Quantitative evaluation of a single sample is valuable for us to combine histopathological and molecular characteristics to comprehensively evaluate the status of the patient. Targeted macrophage treatment has great potential for the individualized precision therapy of UC patients.