Urothelial cancer (UC) is a malignancy originating in the bladder with a challenging prognosis, even in its early disease stages. Currently, the standard of care to cure the disease involves surgical removal of the tumor through radical cystectomy (RC), which is often complemented by pre-operative chemotherapy (NAC, neoadjuvant chemotherapy). In the past two decades, the disease treatment landscape has remained unchanged.

Immune checkpoint inhibitors (ICIs) are a novel treatment type that blocks specific proteins, known as immune checkpoints, that downregulate an immune response. Upon immune checkpoint blockade, immune cells can effectively recognize cancer cells and induce an immune response against cancer cells. In the UC context, early-phase clinical trials have demonstrated both the feasibility and efficacy of pre-operative ICIs and have shown long-lasting clinical responses. Therefore, ICIs hold promise for changing UC clinical management in the future. However, not all patients respond to ICIs, and substantial rates of treatment-related toxicities are observed, highlighting the need for identifying biomarkers that can aid patient stratification.

The studies presented in this thesis focus on elucidating the role of the UC tumor microenvironment (TME) in determining responses to pre-operative treatments, such as chemotherapy and ICIs. Through a comprehensive multi-omics approach, we quantified intrinsic and extrinsic characteristics of UC tumors collected from human samples. We associated them with clinical outcomes such as treatment response and treatment dynamics.@en