Intratumoral Mediated Immunosuppression is Prognostic in Genetically Engineered Murine Models of Glioma and Correlates to Immunotherapeutic Responses

Abstract

Purpose: Preclinical murine model systems used for the assessment of therapeutics have not been predictive of human clinical responses, primarily because their clonotypic nature does not recapitulate the heterogeneous biology and immunosuppressive mechanisms of humans. Relevant model systems with mice that are immunologically competent are needed to evaluate the efficacy of therapeutic agents, especially immunotherapeutics. Experimental Design: Using the RCAS/Ntv-a system, mice were engineered to coexpress platelet-derived growth factor B (PDGF-B) receptor + B-cell lymphoma 2 (Bcl-2) under the control of the glioneuronal specific Nestin promoter. The degree and type of tumor-mediated immunosuppression were determined in these endogenously arising gliomas on the basis of the presence of macrophages and regulatory T cells. The immunotherapeutic agent WP1066 was tested in vivo to assess therapeutic efficacy and immunomodulation. Results: Ntv-a mice were injected with RCAS vectors to express PDGF-B + Bcl-2, resulting in both low- and high-grade gliomas. Consistent with observations in human high-grade gliomas, mice with high-grade gliomas also developed a marked intratumoral influx of macrophages that was influenced by tumor signal transducer and activator of transduction 3 (STAT3) expression. The presence of intratumoral F4/80 macrophages was a negative prognosticator for long-term survival. In mice coexpressing PDGF-B + Bcl-2that were treated with WP1066, there was 55.5% increase in median survival time (P < 0.01), with an associated inhibition of intratumoral STAT3 and macrophages. Conclusions: Although randomization is necessary for including mice in a therapeutic trial, these murine model systems are more suitable for testing therapeutics, especially immunotherapeutics, in the context of translational studies. Clin Cancer Res; 16(23); 5722–33. ©2010 AACR.