Abstract 1611: Intravesical BCG induces CD4 T Cell expansion in an immune competent model of bladder cancer

Abstract

Abstract Intravesical BCG Immunotherapy is the standard of care in treating non-muscle invasive bladder cancer (NMIBC), yet its mechanism of action remains elusive. Both innate and adaptive immune responses have been implicated in BCG activity. While prior research has indirectly demonstrated the importance of T cells and shown a rise in CD4+ T cells in bladder tissue after BCG, T cell subpopulations have not been fully characterized. We investigated the relationship between effector and regulatory T cells in an immune competent, clinically relevant rodent model of bladder cancer. Fischer 344 rats aged 7 weeks received 1.5mg/kg N-Nitroso-N-methylurea (MNU) every other week for 6 weeks (4 doses). Bladder dysplasia began by week 8 and by week 16 the majority of rats had a NMIBC phenotype. Beginning week 8 following the first MNU dose, rats were intravesically administered 0.3ml of BCG (Tice), cisplatin (1mg/ml), Mitomycin C (2mg/ml), MMC+ BCG, or saline (n=10 for all groups) weekly for 6 total doses. Animals were sacrificed at week 16, and bladders were processed for histopathology and digested into single cell suspensions for flow cytometry. Whole transcriptome expression profiling was then performed on sorted CD4 and CD8 cells of post-BCG tumors vs untreated tumors to assess T cell differentiation after BCG. Our data demonstrate that cancer progression in the MNU rat model of bladder cancer is characterized by a decline in the CD8/FoxP3 ratio, consistent with decreased adaptive immunity. By contrast, treatment with intravesical BCG leads to a large, transient rise in the CD4+ T cell population in the urothelium, and is both more effective and immunogenic compared to intravesical chemotherapy. Interestingly, whole transcriptome expression profiling of post-treatment intravesical CD4+ and CD8+ T cells revealed minimal differences in gene expression after BCG treatment. Together, our results suggest that while BCG induces T cell recruitment to the bladder, the T cell phenotype does not markedly change, implying that combining T cell activating agents with BCG might improve clinical activity. Citation Format: Max Kates, Thomas Nirschl, Nikolai Sopko, Noah Hahn, David McConkey, Alex Baras, Charles Drake, Trintiy Bivalacqua. Intravesical BCG induces CD4 T Cell expansion in an immune competent model of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1611. doi:10.1158/1538-7445.AM2017-1611