Tmic-60. cross-species analysis of human and new mouse models of gbm subtypes identifies vista as a promising immunotherapy target

Immunotherapy is a promising treatment modality for GBM; however, clinical trials thus far have failed to provide significant clinical benefit to most patients. GBM is one of the “immune cold” tumors characterized by poor infiltration of T cells and the abundance of immune-suppressive myeloid cells that block T cell infiltration and/or activation. A major bottleneck to developing more effective immunotherapies is the paucity of faithful preclinical models to discover and validate new treatments. Here, we report multi-dimensional analyses of six different transplantable mouse glioma models in the C57BL6/J background that represent the three human GBM molecular subtypes. We performed whole exome sequencing, STR fingerprinting, immune phenotyping, and single-cell RNA-sequencing of each model and confirmed that the new models exhibit highly heterogeneous and immune suppressive TME, similar to human GBM. In addition, we performed cross-species comparisons of glioma and immune cell subtypes between human and mouse GBMs at the single-cell level and demonstrate strong concordances in molecular phenotypes and cellular heterogeneity. These result in qualitative and quantitative differences in the cell: cell communication among different stromal cells and glioma cells in each model, and we propose that these interactions shape the local niche and immune suppressive neighborhoods. Notably, in both human tissues and mouse models, PD1/PDL1 expression is low or sporadic, and, unlike the GL261 model, the new mouse models are resistant to anti-PD1 and CTLA4 treatment in vivo. Finally, we discovered that VISTA is a widely expressed immune checkpoint in both human and mouse GBM and demonstrate the efficacy of anti-VISTA and anti-PD1 combination therapy in the most immune-suppressive mouse model. In summary, we demonstrate the utility of these immune-competent mouse models and nominate anti-VISTA+PD1 treatment as a promising novel combination therapy for GBM.