PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis.
PD-1 is a haploinsufficient suppressor of T cell lymphomagenesis.
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DOI：
10.1038/nature24649
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发表时间：
2017-12-07
期刊：
影响因子：
64.8
通讯作者：
Ruland J
中科院分区：
文献类型：
--
作者：
Wartewig T;Kurgyis Z;Keppler S;Pechloff K;Hameister E;Öllinger R;Maresch R;Buch T;Steiger K;Winter C;Rad R;Ruland J
T细胞非霍奇金淋巴瘤(T-NHL)是一组高度侵袭性、临床转归较差的异质性恶性肿瘤。T-NHL起源于外周T淋巴细胞，通常以T细胞抗原受体(TCR)信号分子的功能获得变异为特征。尽管这些致癌基因的改变被认为是驱动TCR途径来诱导慢性增殖和生存程序，但尚不清楚T细胞是否含有能够抵消这些事件的肿瘤抑制因子。利用人类T细胞淋巴瘤的小鼠模型，我们证明了在淋巴细胞中，致癌TCR信号的急剧加强推动了这些细胞在体内的强劲扩张。然而，这种反应是短暂的，并被细胞内在机制有力地抵消。随后利用T细胞特异性转座子突变进行的全基因组体内筛选发现，编码抑制性受体程序性死亡-1(PD-1)的PDCD1是抑制致癌T细胞信号的主控基因。单等位基因和双等位基因PDCD1缺失也在人类T细胞淋巴瘤中反复出现，频率可超过30%，表明具有很高的临床相关性。从机制上讲，PD-1活性增强了癌前细胞中PTEN的水平，并减弱了AKT和PKC信号。相比之下，PD-1的纯合或杂合缺失允许致癌损伤后T细胞不受限制地生长，并导致体内高度侵袭性淋巴瘤的快速发展，这些淋巴瘤很容易移植给接受者。总之，这些结果表明，抑制性PD-1受体是T-NHL中一种有效的单倍体不足的肿瘤抑制因子，在人类疾病中经常发生变化。这些发现将PD-1的已知生理功能扩展到抗原诱导的T细胞激活后的免疫病理学预防之外，并对T细胞淋巴瘤的治疗和当前在免疫肿瘤学背景下针对PD-1的当前策略具有指导意义。
T cell non-Hodgkin lymphomas (T-NHLs) represent a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T-NHLs originate from peripheral T lymphocytes and are frequently characterized by genetic gain-of-function variants in T cell antigen receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and survival programmes, it remains unclear whether T cells harbour tumour suppressors that can counteract these events. Using a murine model of human T cell lymphoma, we demonstrate that the acute enforcement of oncogenic TCR signalling in lymphocytes drives the strong expansion of these cells in vivo. However, this response is short-lived and robustly counteracted by cell-intrinsic mechanisms. A subsequent genome-wide in vivo screen using T cell-specific transposon mutagenesis identified PDCD1, which encodes the inhibitory receptor Programmed Death-1 (PD-1), as a master gene suppressing oncogenic T cell signalling. Mono- and bi-allelic PDCD1 deletions are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, PD-1 activity enhances PTEN levels and attenuates AKT and PKC signalling in pre-malignant cells. In contrast, a homo- or heterozygous deletion of PD-1 allows unrestricted T cell growth after an oncogenic insult and leads to the rapid development of highly aggressive lymphomas in vivo that are readily transplantable to recipients. Altogether, these results indicate that the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T-NHLs that is frequently altered in human disease. These findings extend the known physiological functions of PD-1 beyond the prevention of immunopathology after antigen-induced T cell activation and have implications for T cell lymphoma therapies and for current strategies that target PD-1 in the broader context of immuno-oncology.
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DOI：
10.1084/jem.20092042
发表时间：
2010-05-10
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Pechloff K;Holch J;Ferch U;Schweneker M;Brunner K;Kremer M;Sparwasser T;Quintanilla-Martinez L;Zimber-Strobl U;Streubel B;Gewies A;Peschel C;Ruland J
通讯作者：
Ruland J
影响因子：
30.8
作者：
da Silva Almeida AC;Abate F;Khiabanian H;Martinez-Escala E;Guitart J;Tensen CP;Vermeer MH;Rabadan R;Ferrando A;Palomero T
通讯作者：
Palomero T
影响因子：
7.8
作者：
Kulpa DA;Lawani M;Cooper A;Peretz Y;Ahlers J;Sékaly RP
通讯作者：
Sékaly RP
影响因子：
4.4
作者：
Chemnitz, JM;Parry, RV;Riley, JL
通讯作者：
Riley, JL
DOI：
10.1093/bioinformatics/btr670
发表时间：
2012-02-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Boeva V;Popova T;Bleakley K;Chiche P;Cappo J;Schleiermacher G;Janoueix-Lerosey I;Delattre O;Barillot E
通讯作者：
Barillot E