Molecular Subtype-Specific Immunocompetent Models of High-Grade Urothelial Carcinoma Reveal Differential Neoantigen Expression and Response to Immunotherapy

Cancer Res. 2018 Jul 15;78(14):3954-3968. doi: 10.1158/0008-5472.CAN-18-0173. Epub 2018 May 21.

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology*
  • Carcinoma / immunology*
  • Disease Models, Animal
  • Humans
  • Immunocompetence / immunology*
  • Immunotherapy / methods
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / immunology
  • T-Lymphocytes / immunology
  • Tumor Microenvironment / immunology
  • Urinary Bladder Neoplasms / immunology
  • Urologic Neoplasms / immunology*
  • Urothelium / immunology*

Substances

  • Antigens, Neoplasm
  • Programmed Cell Death 1 Receptor