Bypassing resistance mechanism to immunotherapy in bladder cancer

Swiss partners

• Université de Genève: Hajar El Ahanidi (main applicant), Camilla Jandus

Partners in the MENA region

• Centre National de l'Energie, des Sciences et des Techniques Nucléaires, Maroc: Mohammed El Mzibri (main applicant), Mohammed Attaleb

Presentation of the projet

Bladder cancer (BC) is a disease with several molecular and pathological pathways, reflecting different behaviors depending on the clinical staging of the tumor and the molecular type. It has been shown that BC is one of the cancers with the most important load of DNA damage. In fact, due to its “reservoir-like” function, the bladder is continuously in contact with toxic molecules and metabolites and subjected to many types of inflammatory and genotoxic agents.

Immunotherapy is a powerful strategy to treat cancer by harnessing the body’s immune system to generate or augment an immune response against it. During the last decade, novel tumor immunotherapeutic approaches have revolutionized cancer treatment. The use of immune checkpoint inhibitors (ICIs) against immune escape mechanisms has been approved for treatment of different tumor entities and has been shown to consistently improve the overall survival, yet only in a limited number of patients and tumor types.

In bladder cancer, only 15–25% of patients with advanced disease respond to therapy, and even those who initially respond may later develop acquired resistance. The mode of action of ICIs has been almost exclusively linked to their effect on checkpoint expressing immune cells, while much less is known on immune checkpoint ligand - dependent resistance to ICIs. As extensive efforts have been made to understand how PD1 signaling and regulation on T-cell play a role in tumor resistance to ICIs; here, we propose to tackle the problematic from a novel perspective. In this project, we speculate on an innovative resistance mechanism to anti-PD1/L1 treatment in bladder cancer that plays a role in the initiation and reinforcement of resistance occurring at different phases of tumorigenesis.

Based on this knowledge and preliminary data, we hypothesize on the existence of a therapeutically targetable crosstalk between DNA damage response pathways and PD1-Ligands, and we aim to understand the mechanistic pathways underlying resistance to anti-PD-Ls’ therapy in bladder. Overall, we expect this project to provide novel facets of our understanding of ICIs resistance mechanisms in cancer, and to identify novel therapeutic strategy for bladder cancer patients and beyond.