Molecular Subtype-Specific Immunocompetent Models of High-Grade Urothelial Carcinoma Reveal Differential Neoantigen Expression and Response to Immunotherapy.
Cancer Res
; 78(14): 3954-3968, 2018 07 15.
Article
in En
| MEDLINE
| ID: mdl-29784854
ABSTRACT
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 memoryregulatory 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Carcinoma
/
Urologic Neoplasms
/
Urothelium
/
Immunocompetence
/
Antigens, Neoplasm
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cancer Res
Year:
2018
Document type:
Article