Abstract A11: Generation and characterization of immune-competent syngeneic model of muscle-invasive bladder cancer (MIBC)

Abstract

Abstract Immunologically, MIBC tumors can be divided into inflamed and noninflamed phenotype. Inflamed tumors show high immune cell infiltration. In contrast, noninflamed tumors have little to no immune infiltration. Clinical evidence shows that response to therapy, particularly immune therapy, is associated with the immune phenotype of the tumor. In our preliminary analysis of the TCGA tumor expression data, we observed that patients with high CD8 T-cell infiltration expression signature show an improved overall survival irrespective of treatment. To study the molecular and immunologic drivers of CD8+ T-cell tumor infiltration in MIBC, we have generated immune-competent syngeneic models of bladder cancer. The mouse models were generated by inducing invasive disease by treating C57BL/6 mice with carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). The induced tumors were grafted into sex-matched immune-competent syngeneic hosts establishing allograft tumor lines. The models represent different clinical subtypes both molecularly and histologically. Currently we have 8 different models with squamous, sarcamatoid, or a more differentiated phenotype. RNA-seq analysis of the tumor lines was used to classify the models into basal-like and luminal-like tumors using the TCGA classifier system. Using the RNA-seq data, we applied a deconvolution algorithm to identify models that had inflamed or noninflamed immune phenotype. Flow cytometry data indicate that the inflamed tumors have a higher infiltration of the myeloid population. We treated 4/8 models with cisplatin, the current standard of care. The models show variable response to cisplatin, indicating the variability between the different models. In conclusion, we have successfully developed immune-competent syngeneic mouse models of MIBC that can be used to study the molecular and immune-driven processes of the disease. Citation Format: Shruti D. Shah, Bryan Gillard, Ellen Karasik, Michelle Wrobel, Michael T. Moser, Barbara A. Foster. Generation and characterization of immune-competent syngeneic model of muscle-invasive bladder cancer (MIBC) [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 A11.