Background and Objective: Muscle-invasive bladder cancer (MIBC) is a complex disease for which perioperative chemotherapy followed by radical cystectomy is a standard treatment. In recent years new therapy options for advanced urothelial tumors have emerged, representing a personalized medicine approach for patients. For example, targeting fibroblast growth factor receptors (FGFR) as well as restoring antitumor activity using PD-1/PD-L1 inhibitors are currently being evaluated in clinical trials and show promising results. Our present goal in this study was to assess the relationship of FGFR3-gene alterations, immune cell types, gene expression of checkpoint inhibitors like PD-L1/PD-1, and immune-related genes in MIBC to gain insight into significant differential expression.
Materials and Methods: We analyzed the TCGA cohort (n=407). Tumors were identified with activating FGFR3-gene alterations (FGFR3-altered: mutation, amplification, fusion, gain). A comparison was performed between tumors with FGFR3-altered or wild-type tumors and tumor mutational burden (TMB), neoantigen load, immune checkpoint, and immune-related gene expression as well as specific immune cell populations using the CIBERSORT-algorithm.
Results: Activating FGFR3-altered tumors showed significantly less TMB and neoantigen load compared to wild-type cases (p=0.037 and p=0.04). Tumors with high expression of PD-1, PD-L1, CTLA4, and IDO1 were predominately not FGFR3-altered (p<0.0001). Additionally, expression of immune-related genes like CD3Z, CD8A, FOXP3 and amounts of specific immune cell populations were significantly inversely associated with an FGFR3-altered status.
Conclusion: Strikingly, our analysis demonstrates that activating FGFR3 gene alterations in MIBC show low immune checkpoint and immune-related gene expression as well as low amounts of immune cells, demonstrating association with an uninflamed tumor microenvironment. Therefore, combination therapies targeting FGFR3 and, e.g., PD-1/PD-L1 might not be effective. It will be essential to validate these results in another MIBC cohort as well as unravel the role of aberrant signaling of FGFR3.
Citation Format: Veronika Weyerer, Robert Stoehr, Pamela Strissel, Reiner Strick, Christian Bolenz, Arndt Hartmann, Philipp Erben, Markus Eckstein. Uninflamed immunologic microenvironment of muscle-invasive bladder cancer associates with activating FGFR3 gene alterations [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A15.