Sanda, Tarun2024-01-112024-01-112024-01-11http://hdl.handle.net/10393/45824http://dx.doi.org/10.20381/ruor-30028The inhibitors of apoptosis (IAP) proteins regulate cell death signaling cascades. Smac mimetic (SM) compounds are antagonists of these proteins and are being evaluated for their anti-cancer efficacy and immunomodulatory effects. Here, I adopted an orthotopic murine model of urothelial carcinoma (MB49) resistant to prominent immune-stimulating therapies BCG mycobacterium and PD-1/PD-L1 checkpoint blockade. I found treatment with a monovalent SM, LCL161, generated T lymphocyte-dependent cures of MB49, retaining potent anti-tumour immune memory and significantly improving overall survival benefit. Separately, I report SM treatment modulates multiple components comprising the cellular adaptive immune response. Specifically, I found SM promoting the expansion of antigen-presenting cells (APCs) in vitro and enabling T lymphocyte priming in vivo. I evaluated SM in combination with concurrent immune checkpoint blockade. The combination of SM with a monoclonal antibody targeting cytotoxic T lymphocyte-associated protein 4 (CTLA-4, 9h10 clone) potentiated anticancer immunity, curing all tested subjects of MB49. I verified Fc receptor-dependent intratumoural regulatory T cell depletion as a required mechanism for enhancing survival probability with the combination of SM and anti-CTLA-4. The further evaluation of mechanisms responsible for SMs stimulating immunity will promote their clinical application for cancer therapy.enThesis