Department of Neurosurgery and.
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
J Clin Invest. 2020 Oct 1;130(10):5257-5271. doi: 10.1172/JCI138760.
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.
免疫治疗策略在神经肿瘤学中越来越重要，阐明导致治疗耐药的逃逸机制至关重要。我们通过比较免疫活性与免疫缺陷小鼠中的神经胶质瘤生长，研究了免疫压力对克隆动力学和免疫逃逸特征的影响。与免疫缺陷 Pfp-/- Rag2-/- 小鼠相比，携带神经胶质瘤的 WT 和 Pd-1-/- 小鼠的存活率显著延长。虽然 Pfp-/- Rag2-/- 小鼠中的肿瘤具有高度的多克隆性，但 WT 和 Pd-1-/- 小鼠中的免疫编辑肿瘤显示出克隆性降低，出现免疫逃逸克隆。WT 小鼠中的肿瘤细胞表现出 IFN-γ 介导的反应特征，其中涉及免疫抑制的基因上调。肿瘤浸润性基质细胞（包括巨噬细胞/小胶质细胞）对免疫抑制特征的贡献甚至强于实际的肿瘤细胞。在人类患者中也反映了鉴定出的鼠免疫逃逸特征，并与不良预后相关。总之，免疫压力深刻地影响了恶性神经胶质瘤的克隆组成和基因调控。
