Modeling tumor immunity of mouse glioblastoma by exhausted CD8+ T cells

Sci Rep. 2018 Jan 9;8(1):208. doi: 10.1038/s41598-017-18540-2.

Abstract

T cell exhaustion occurs during chronic infection and cancers. Programmed cell death protein-1 (PD-1) is a major inhibitory checkpoint receptor involved in T cell exhaustion. Blocking antibodies (Abs) against PD-1 or its ligand, PD-L1, have been shown to reverse T cell exhaustion during chronic infection and cancers, leading to improved control of persistent antigen. However, modeling tumor-specific T cell responses in mouse has been difficult due to the lack of reagents to detect and phenotype tumor-specific immune responses. We developed a novel mouse glioma model expressing a viral epitope derived from lymphocytic choriomeningitis virus (LCMV), which allowed monitoring of tumor-specific CD8 T-cell responses. These CD8 T cells express high levels of PD-1 and are unable to reject tumors, but this can be reversed by anti-PD-1 treatment. These results suggest the efficacy of PD-1 blockade as a treatment for glioblastoma, an aggressive tumor that results in a uniformly lethal outcome. Importantly, this new syngeneic tumor model may also provide further opportunities to characterize anti-tumor T cell exhaustion and develop novel cancer immunotherapies.

Publication types

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

MeSH terms

  • Animals
  • Brain Neoplasms / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Epitopes / immunology
  • Glioblastoma / immunology*
  • Lymphocytic choriomeningitis virus / genetics
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism

Substances

  • Epitopes
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor