Molecular Subtype-Specific Immunocompetent Models of High-Grade Urothelial Carcinoma Reveal Differential Neoantigen Expression and Response to Immunotherapy.
Ryoichi SaitoChristof C SmithTakanobu UtsumiLisa M BixbyJordan KardosSara E WobkerKyle G StewartShengjie ChaiUjjawal ManochaKevin M ByrdJeffrey S DamrauerScott E WilliamsBenjamin G VincentWilliam Y KimPublished in: Cancer research (2018)
High-grade urothelial cancer contains intrinsic molecular subtypes that exhibit differences in underlying tumor biology and can be divided into luminal-like and basal-like subtypes. We describe here the first subtype-specific murine models of bladder cancer and show that Upk3a-CreERT2; Trp53L/L; PtenL/L; Rosa26LSL-Luc (UPPL, luminal-like) and BBN (basal-like) tumors are more faithful to human bladder cancer than the widely used MB49 cells. Following engraftment into immunocompetent C57BL/6 mice, BBN tumors were more responsive to PD-1 inhibition than UPPL tumors. Responding tumors within the BBN model showed differences in immune microenvironment composition, including increased ratios of CD8+:CD4+ and memory:regulatory T cells. Finally, we predicted and confirmed immunogenicity of tumor neoantigens in each model. These UPPL and BBN models will be a valuable resource for future studies examining bladder cancer biology and immunotherapy.Significance: This work establishes human-relevant mouse models of bladder cancer. Cancer Res; 78(14); 3954-68. ©2018 AACR.
Keyphrases
- high grade
- regulatory t cells
- low grade
- endothelial cells
- papillary thyroid
- mouse model
- stem cells
- poor prognosis
- induced apoptosis
- induced pluripotent stem cells
- dendritic cells
- pluripotent stem cells
- squamous cell carcinoma
- cancer therapy
- oxidative stress
- single cell
- adipose tissue
- muscle invasive bladder cancer
- gene expression
- working memory
- cell death
- dna methylation
- metabolic syndrome
- cell proliferation
- childhood cancer
- insulin resistance
- cord blood