Ricerc@Sapienza

Intravesical immunotherapy with bacillus Calmette-Guérin (BCG) has been used for nearly four decades to treat non-muscle-invasive bladder cancer. Despite treatment, a significant proportion of patients fails to respond and ultimately require more aggressive treatment. Early identification of high-risk patients who might not benefit from BCG treatment is critical, since delaying radical surgery definitely worsens patient outcome. Although the exact mechanism of action of BCG is not completely understood, it is now recognized that the antitumor effects of BCG are produced by the complex interplay between the direct effects on tumor cells by BCG infection and the host immune response. It is now well recognized that a competent immune system and functional T-cells subsets amongst other immune cells are required for response to BCG. Immune checkpoint molecules play a critical role in regulating T cell functionality after TCR/MHC signaling, to prevent bystander damage from unrestrained T-cell activity. Inhibitory T cell co-receptors, such as CTLA-4 and PD-1, cause T cell anergy and apoptosis, impeding anti-tumor immunity. Cancers use the PD-L1 pathway to inhibit immune responses by the ectopic expression of inhibitory ligands that regulate T cell activation. PD-L1 on bladder cancer cells is increasingly expressed with advancing local tumor stage, and a strong association has been described between PD-L1 overexpression and cancer progression, perhaps facilitating the eventual loss of BCG effectiveness over time. Whether the upregulation of PD-L1 expression in tumor tissues might be induced in response of BCG instillations, and whether it may contribute to unresponsiveness or relapse following BCG therapy represent the main aims of the present proposal. PD-L1 expression on circulating tumor cells through serial liquid biopsies will be also analysed as an hypothetical biomarker of treatment resistance.