Inhibition of the adenosine pathway - a new approach to boost immunotherapy in advanced bladder cancer

Overview

Project Summary

Despite the impressive success of immune-checkpoint inhibitors (ICI) in advanced/metastatic bladder cancer (BC), only a minority derive clinical benefit, suggesting other factor besides immune-checkpoints, negatively influence T-cell-mediated immune response. Hypoxia-driven adenosine signaling is a key metabolic pathway exploited by tumors, to suppress anti-tumor immunity by disabling immune effector functions while exerting immunosuppression. Preliminary data obtained BC patients revealed in virtually all samples, the expression of the hypoxic marker HIF-1a and its direct downstream-target CD73 (rate-limiting ecto-enzyme for adenosine generation), considered master regulators of hypoxia-driven adenosinergic pathway. Indeed, cases with high HIF-1a/CD73 labeling scores, displayed a trend towards poor CD8+T infiltration, higher percentage of PD-L1-expressing tumor cells and of PD-1-positive lymphocytes and poor response to anti-PD-L1 therapy.

We hypothesize the adenosinergic pathway constitute an immunosuppressive mechanism and a major cause of clinical failure of ICI and co-targeting adenosinergic axis while relieving immunosuppression enhance the therapeutic efficacy of ICI in BC.

Main Goals

• Decipher the role of adenosinergic pathway in the profile of infiltrating-immune cells, using a pre-clinical model.
• Investigate the anti-tumor synergistic activity of co-targeting the adenosine pathway with immune checkpoint inhibitors in a pre-clinical model
• Decoding the adenosine-immunosuppressive pathway and its association with response to anti-PD-1/PD-L1 therapy in BC patients

Project Details