Dysregulated FGFR3 signaling alters the immune landscape in bladder cancer and presents therapeutic possibilities in an agent-based model

Abstract

Bladder cancer is an increasingly prevalent global disease that continues to cause morbidity and mortality despite recent advances in treatment. Immune checkpoint inhibitors (ICI) and fibroblast growth factor receptor (FGFR)-targeted therapeutics have had modest success in bladder cancer when used as monotherapy. Emerging data suggests that the combination of these two therapies could lead to improved clinical outcomes, but the optimal strategy for combining these agents remains uncertain. Mathematical models, specifically agent-based models (ABMs), have shown recent successes in uncovering the multiscale dynamics that shape the trajectory of cancer. They have enabled the optimization of treatment methods and the identification of novel therapeutic strategies. To assess the combined effects of anti-PD-1 and anti-FGFR3 small molecule inhibitors (SMI) on tumor growth and the immune response, we built an ABM that captures key facets of tumor heterogeneity and CD8⁺ T cell phenotypes, their spatial interactions, and their response to therapeutic pressures. Our model quantifies how tumor antigenicity and FGFR3 activating mutations impact disease trajectory and response to anti-PD-1 antibodies and anti-FGFR3 SMI. We find that even a small population of weakly antigenic tumor cells bearing an FGFR3 mutation can render the tumor resistant to combination therapy. However, highly antigenic tumors can overcome therapeutic resistance mediated by FGFR3 mutation. The optimal therapy depends on the strength of the FGFR3 signaling pathway. Under certain conditions, ICI alone is optimal; in others, ICI followed by anti-FGFR3 therapy is best. These results indicate the need to quantify FGFR3 signaling and the fitness advantage conferred on bladder cancer cells harboring this mutation. This ABM approach may enable rationally designed treatment plans to improve clinical outcomes.

Keywords: CD8+ T cells; FGFR3; Fas/Fas ligand; agent-based model; antigenicity; bladder cancer; immune checkpoint inhibition; perforin/granzyme.