Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion.
Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion.
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DOI：
10.1016/j.cell.2021.03.023
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发表时间：
2021-04-29
期刊：
影响因子：
64.5
通讯作者：
Pollard SM
中科院分区：
文献类型：
--
作者：
Gangoso E;Southgate B;Bradley L;Rus S;Galvez-Cancino F;McGivern N;Güç E;Kapourani CA;Byron A;Ferguson KM;Alfazema N;Morrison G;Grant V;Blin C;Sou I;Marques-Torrejon MA;Conde L;Parrinello S;Herrero J;Beck S;Brandner S;Brennan PM;Bertone P;Pollard JW;Quezada SA;Sproul D;Frame MC;Serrels A;Pollard SM
多形性胶质母细胞瘤（GBM）是一种侵袭性脑肿瘤，目前的免疫治疗方法尚未成功。在这里，我们探讨免疫逃避GBM的机制。通过将GBM干细胞（GSCs）连续移植到免疫活性宿主中，我们揭示了GSCs通过建立增强的免疫抑制肿瘤微环境而获得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，而是通过表观遗传免疫编辑过程引起的，其中在免疫攻击后，GSC中的稳定转录和表观遗传变化被强制执行。这些变化启动了骨髓相关的转录程序，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GSC中鉴定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，在最具侵袭性的间充质GBM亚型中驱动获得性免疫逃避程序。疾病相关的TME在免疫活性GBM小鼠模型中重现免疫攻击后GSC中发生转录组的稳定重构免疫逃避性GSC部署“髓样拟态”以建立髓样富集的TME获得的转录变化与表观遗传免疫编辑过程一致胶质母细胞瘤干细胞通过表观遗传免疫编辑而不是亚克隆选择部署髓样拟态程序，以驱动骨髓富集的肿瘤微环境，从而实现免疫逃避和肿瘤进展。
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. Disease-relevant TME is recapitulated in immunocompetent GBM mouse models Stable reconfiguration of the transcriptome occurs in GSCs following immune attack Immune evasive GSCs deploy “myeloid mimicry” to establish a myeloid-enriched TME Acquired transcriptional changes consistent with a process of epigenetic immunoediting Glioblastoma stem cells deploy a myeloid mimicry program through epigenetic immunoediting, rather than subclonal selection, to drive a myeloid-enriched tumor microenvironment, thereby enabling immune evasion and tumor progression.
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影响因子：
64.8
作者：
Capper D;Jones DTW;Sill M;Hovestadt V;Schrimpf D;Sturm D;Koelsche C;Sahm F;Chavez L;Reuss DE;Kratz A;Wefers AK;Huang K;Pajtler KW;Schweizer L;Stichel D;Olar A;Engel NW;Lindenberg K;Harter PN;Braczynski AK;Plate KH;Dohmen H;Garvalov BK;Coras R;Hölsken A;Hewer E;Bewerunge-Hudler M;Schick M;Fischer R;Beschorner R;Schittenhelm J;Staszewski O;Wani K;Varlet P;Pages M;Temming P;Lohmann D;Selt F;Witt H;Milde T;Witt O;Aronica E;Giangaspero F;Rushing E;Scheurlen W;Geisenberger C;Rodriguez FJ;Becker A;Preusser M;Haberler C;Bjerkvig R;Cryan J;Farrell M;Deckert M;Hench J;Frank S;Serrano J;Kannan K;Tsirigos A;Brück W;Hofer S;Brehmer S;Seiz-Rosenhagen M;Hänggi D;Hans V;Rozsnoki S;Hansford JR;Kohlhof P;Kristensen BW;Lechner M;Lopes B;Mawrin C;Ketter R;Kulozik A;Khatib Z;Heppner F;Koch A;Jouvet A;Keohane C;Mühleisen H;Mueller W;Pohl U;Prinz M;Benner A;Zapatka M;Gottardo NG;Driever PH;Kramm CM;Müller HL;Rutkowski S;von Hoff K;Frühwald MC;Gnekow A;Fleischhack G;Tippelt S;Calaminus G;Monoranu CM;Perry A;Jones C;Jacques TS;Radlwimmer B;Gessi M;Pietsch T;Schramm J;Schackert G;Westphal M;Reifenberger G;Wesseling P;Weller M;Collins VP;Blümcke I;Bendszus M;Debus J;Huang A;Jabado N;Northcott PA;Paulus W;Gajjar A;Robinson GW;Taylor MD;Jaunmuktane Z;Ryzhova M;Platten M;Unterberg A;Wick W;Karajannis MA;Mittelbronn M;Acker T;Hartmann C;Aldape K;Schüller U;Buslei R;Lichter P;Kool M;Herold-Mende C;Ellison DW;Hasselblatt M;Snuderl M;Brandner S;Korshunov A;von Deimling A;Pfister SM
通讯作者：
Pfister SM
影响因子：
64.5
作者：
Benci JL;Xu B;Qiu Y;Wu TJ;Dada H;Twyman-Saint Victor C;Cucolo L;Lee DSM;Pauken KE;Huang AC;Gangadhar TC;Amaravadi RK;Schuchter LM;Feldman MD;Ishwaran H;Vonderheide RH;Maity A;Wherry EJ;Minn AJ
通讯作者：
Minn AJ
影响因子：
2.7
作者：
Didion JP;Martin M;Collins FS
通讯作者：
Collins FS
DOI：
10.1101/sqb.2016.81.030973
发表时间：
2016
期刊：
Cold Spring Harbor symposia on quantitative biology
影响因子：
--
作者：
Alcantara Llaguno SR;Xie X;Parada LF
通讯作者：
Parada LF
DOI：
10.1073/pnas.97.1.91
发表时间：
2000-01-04
影响因子：
11.1
作者：
Contursi, C;Wang, IM;Ozato, K
通讯作者：
Ozato, K