Project description:Immunotherapeutic strategies are increasingly important in neuro-oncology and the elucidation of escape mechanisms which lead to treatment resistance is crucial. We investigated the impact of immune pressure on the clonal dynamics and immune escape signature by comparing glioma growth in immunocompetent versus immunodeficient mice. Glioma-bearing wildtype and PD-1-/- mice survived significantly longer than immunodeficient Pfp/Rag2-/- mice. While tumors in Pfp/Rag2-/- mice were highly polyclonal, immunoedited tumors in WT and PD-1-/- mice displayed reduced clonality with emergence of immune escape clones. Tumor cells in wildtype mice were distinguished by an interferon-gamma-mediated response signature with upregulation of genes involved in immunosuppression. Tumor-infiltrating stromal cells, which include macrophages/microglia, contributed even stronger to the immunosuppressive signature than the actual tumor cells. The identified murine immune escape signature was reflected in human patients and correlated with poor survival. In conclusion, cancer immune pressure profoundly shapes the clonal composition and gene regulation in malignant gliomas.
Project description:Immunotherapeutic strategies are increasingly important in neuro-oncology and the elucidation of escape mechanisms which lead to treatment resistance is crucial. We investigated the impact of immune pressure on the clonal dynamics and immune escape signature by comparing glioma growth in immunocompetent versus immunodeficient mice. Glioma-bearing wildtype and PD-1-/- mice survived significantly longer than immunodeficient Pfp/Rag2-/- mice. While tumors in Pfp/Rag2-/- mice were highly polyclonal, immunoedited tumors in WT and PD-1-/- mice displayed reduced clonality with emergence of immune escape clones. Tumor cells in wildtype mice were distinguished by an interferon-gamma-mediated response signature with upregulation of genes involved in immunosuppression. Tumor-infiltrating stromal cells, which include macrophages/microglia, contributed even stronger to the immunosuppressive signature than the actual tumor cells. The identified murine immune escape signature was reflected in human patients and correlated with poor survival. In conclusion, cancer immune pressure profoundly shapes the clonal composition and gene regulation in malignant gliomas.
Project description:Immunotherapeutic strategies are increasingly important in neuro-oncology, and the elucidation of escape mechanisms that lead to treatment resistance is crucial. We investigated the impact of immune pressure on the clonal dynamics and immune escape signature by comparing glioma growth in immunocompetent versus immunodeficient mice. Glioma-bearing WT and Pd-1-/- mice survived significantly longer than immunodeficient Pfp-/- Rag2-/- mice. While tumors in Pfp-/- Rag2-/- mice were highly polyclonal, immunoedited tumors in WT and Pd-1-/- mice displayed reduced clonality with emergence of immune escape clones. Tumor cells in WT mice were distinguished by an IFN-γ-mediated response signature with upregulation of genes involved in immunosuppression. Tumor-infiltrating stromal cells, which include macrophages/microglia, contributed even more strongly to the immunosuppressive signature than the actual tumor cells. The identified murine immune escape signature was reflected in human patients and correlated with poor survival. In conclusion, immune pressure profoundly shapes the clonal composition and gene regulation in malignant gliomas.
Project description:There is little overlap on publicily avaiable gene signatures and it is unclear how relevant these are to glioma biology. MYC is a very dynamically regulated gene, and it's gene signature will vary with respect to cell context. To determine what genes fall within the MYC signature of glioma, we performed ChIP-SEQ upon 4 different glioma PDX with two different MYC antibodies. The overlapping enriched genes will provide context of a MYC signature within the context of glioma.
Project description:In mouse models of PDGF-driven glioma where Notch is tumor-suppressive, we find that Notch activity shapes interferon-response in tumor cells and the local immune microenvironment early during tumor progression. Notch inhibition disturbs cytokine expression by tumor cells, altering recruitment and activation of immune cell populations and favoring hyper-proliferative "immune niche" independent growth. Genetic inactivation of Notch in glioma cells also attenuates their response to interferon-gamma, establishing a non-cell autonomous inhibitory feedback loop that further promotes immune evasion and aggressiveness. Hence, we propose that Notch signaling levels in tumor cells are key to orchestrate immune escape and microenvironment independency during brain tumor formation.