TMOD-20. ESTABLISHMENT OF A BRAIN TUMOR MODEL WITH DYSFUNCTIONAL TUMOR IMMUNITY IN MICE AS A PLATFORM FOR IMMUNOTHERAPEUTIC EVALUATION

Abstract

Several clinical trials are currently underway for patients with newly diagnosed and recurrent glioblastoma to reinvigorate tumor immunity using immune-checkpoint blockade. However, the CNS is immunologically unique in its maintenance of an immunosuppressive environment, to protect brain cells from autoimmunity and inflammation. Thus, immunotherapy of brain tumors requires novel regimens to overcome tumor immuno-suppression. Suitable preclinical animal models with exhausted tumor-specific immunity are currently not available. We thus hypothesized that a chronic LCMV (cLCMV) strain that induces T cell exhaustion in mice may be co-opted to model the impaired immunity that characterizes brain tumors. In this model, naïve and cLCMV-infected mice failed to reject a challenge with glioma in brain when murine glioma cells express one of LCMV antigens (VA-glioma) that are presented via MHC-I. In contrast, mice preimmunized with the acutely-controlled LCMV (aLCMV) strain did reject VA-glioma. In fact, in vitro co-culture of lymphocytes and glioma cells, and in vivo TIL analyses suggested that VA-glioma failed to induce CD8+ T cell responses in cLCMV-mice, in contrast to the robust CD8+ T cell response in aLCMV-mice. Furthermore, cLCMV-specific CD8 T cells lacked a central memory T cell phenotype (CD44+, CD62L-, CD127-) and expressed significantly high levels of PD-1. Treatment with anti-PD1, but not isotype control antibody, successfully reinvigorated and restored antitumor immunity in cLCMV-mice that received VA-glioma cells. PD-1 blockade led to significantly improved survival. However, this treatment did not show a therapeutic effect in cLCMV-mice that received parental glioma cells that don’t express the viral antigen. These data strongly suggest that PD-1 blockade is effective in brain tumors that induce impaired tumor-specific T cell immunity. In conclusion, this novel mouse model may be useful to screen for novel immune checkpoint inhibitors and combination regimes in the setting of a single dysfunctional CD8 T cell response.