Centre for Regenerative Medicine, Institute for Regeneration and Repair, University of Edinburgh, 5 Little France Drive, Edinburgh EH16 4UU, UK; CRUK Edinburgh Centre, Institute of Genetics and Molecular Medicine, Crewe Road South, University of Edinburgh, Edinburgh EH42XR, UK.
Cancer Immunology Unit, Research Department of Haematology, University College London Cancer Institute, London WC1E 6BT, UK.
Cell. 2021 Apr 29;184(9):2454-2470.e26. doi: 10.1016/j.cell.2021.03.023. Epub 2021 Apr 14.
Glioblastoma multiforme (GBM) is an aggressive brain tumor for which current immunotherapy approaches have been unsuccessful. Here, we explore the mechanisms underlying immune evasion in GBM. By serially transplanting GBM stem cells (GSCs) into immunocompetent hosts, we uncover an acquired capability of GSCs to escape immune clearance by establishing an enhanced immunosuppressive tumor microenvironment. Mechanistically, this is not elicited via genetic selection of tumor subclones, but through an epigenetic immunoediting process wherein stable transcriptional and epigenetic changes in GSCs are enforced following immune attack. These changes launch a myeloid-affiliated transcriptional program, which leads to increased recruitment of tumor-associated macrophages. Furthermore, we identify similar epigenetic and transcriptional signatures in human mesenchymal subtype GSCs. We conclude that epigenetic immunoediting may drive an acquired immune evasion program in the most aggressive mesenchymal GBM subtype by reshaping the tumor immune microenvironment.
多形性胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，目前的免疫疗法方法都不成功。在这里，我们探讨了 GBM 中免疫逃避的机制。通过将 GBM 干细胞（GSCs）连续移植到免疫活性宿主中，我们发现 GSCs 通过建立增强的免疫抑制肿瘤微环境，获得了逃避免疫清除的能力。从机制上讲，这不是通过肿瘤亚克隆的遗传选择引起的，而是通过一种表观遗传免疫编辑过程，其中 GSCs 中的稳定转录和表观遗传变化在免疫攻击后被强制实施。这些变化引发了与髓样细胞相关的转录程序，导致肿瘤相关巨噬细胞的募集增加。此外，我们在人类间充质亚型 GSCs 中发现了类似的表观遗传和转录特征。我们得出结论，表观遗传免疫编辑可能通过重塑肿瘤免疫微环境，驱动最具侵袭性的间充质 GBM 亚型获得性免疫逃避程序。
