Investigating immune modulation of molecular subtypes of bladder cancer in response to chemotherapy Public Deposited

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  • March 19, 2019
Creator
  • Kardos, Jordan
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
Abstract
  • Urinary bladder cancer is the ninth most common malignancy, with ~77,000 new cases and ~16,000 deaths in the United States annually. Muscle-invasive bladder cancer has been described as a heterogeneous disease and several groups have identified intrinsic molecular subtypes. Here, we characterize the claudin-low, molecular subtype of high-grade bladder cancer. Claudin-low bladder tumors are defined by high levels of epithelial-to-mesenchymal transition (EMT), enrichment for tumor initiating cell (TIC) signatures, and low expression levels of tight-junction claudins. Furthermore, we find that claudin-low tumors are highly enriched across all immune gene signatures examined, but also express high levels of immune checkpoint molecules. In contrast to melanoma and non–small-cell lung cancer, the predicted neoantigen burden does not correlate with immune infiltration in bladder cancer. Standard of care for muscle invasive bladder cancer is combination, platinum-based chemotherapy; however treatment with immune checkpoint inhibitors has also been shown to be effective in both platinum refractory as well as platinum ineligible patients. We describe the comprehensive genomic characterization of urachal adenocarcinoma and the first report of global RNA expression profiling of urachal tumors. We find that urachal tumors molecularly resemble colorectal cancer at the level of gene expression and validate previous reports that have shown that urachal tumors harbor genomic alterations in KRAS, APC, and SMAD2/SMAD4 found in colorectal cancer. Our transcriptome studies reinforce the notion from genomic studies that urachal adenocarcinomas resemble colorectal cancer. We further report that these rare tumors have mutations in DNA Mismatch Repair (MMR) proteins and POLE and describe the successful treatment of a patient with the anti–PD-L1 antibody atezolizumab. Our studies and case report highlight the potential utility of precision oncology in rare tumor types that have no clear standard of care therapy. Finally, we describe the effects of cisplatin-based chemotherapy on the tumor microenvironment. We find that Gemcitabine and Cisplatin (GemCis) and Methotrexate, Vinblastine, Adriamycin, and Cisplatin (MVAC) treatment, the two main frontline chemotherapeutic regimens approved for muscle invasive bladder cancer, have differing effects on the tumor microenvironment and that the luminal and basal molecular subtypes have different responses to therapy. MVAC treatment in luminal tumors in particular induces significantly higher levels of immune infiltration and corresponding immune suppression than GemCis treatment. We further show that this effect appears to be induced by a misregulation of the cytokine expression and induction of EMT, and that methotrexate treatment alone, through its inhibition of dihydrofolate reductase, is sufficient to induce a mesenchymal and immune-infiltrated phenotype. In aggregate this work has important implications for how MVAC and GemCis are combined with immune checkpoint blockade.
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  • In Copyright
Advisor
  • Parker, Joel
  • Baldwin, Albert
  • Davis, Ian
  • Kim, William
  • Vaziri, Cyrus
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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