Wartewig Tim, Kurgyis Zsuzsanna, Keppler Selina, Pechloff Konstanze, Hameister Erik, Öllinger Rupert, Maresch Roman, Buch Thorsten, Steiger Katja, Winter Christof, Rad Roland, Ruland Jürgen
Institut für Klinische Chemie und Pathobiochemie, Klinikum rechts der Isar, Technische Universität München, 81675 München, Germany.
TranslaTUM, Center for Translational Cancer Research, Technische Universität München, 81675 München, Germany.
Nature. 2017 Dec 7;552(7683):121-125. doi: 10.1038/nature24649. Epub 2017 Nov 15.
T cell non-Hodgkin lymphomas are a heterogeneous group of highly aggressive malignancies with poor clinical outcomes. T cell lymphomas originate from peripheral T cells and are frequently characterized by genetic gain-of-function variants in T cell receptor (TCR) signalling molecules. Although these oncogenic alterations are thought to drive TCR pathways to induce chronic proliferation and cell survival programmes, it remains unclear whether T cells contain tumour suppressors that can counteract these events. Here we show that the acute enforcement of oncogenic TCR signalling in lymphocytes in a mouse model of human T cell lymphoma 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 that suppresses oncogenic T cell signalling. Mono- and bi-allelic deletions of PDCD1 are also recurrently observed in human T cell lymphomas with frequencies that can exceed 30%, indicating high clinical relevance. Mechanistically, the activity of PD-1 enhances levels of the tumour suppressor PTEN and attenuates signalling by the kinases AKT and PKC in pre-malignant cells. By 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. Thus, the inhibitory PD-1 receptor is a potent haploinsufficient tumour suppressor in T cell lymphomas 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.
T细胞非霍奇金淋巴瘤是一组异质性很强的侵袭性恶性肿瘤,临床预后较差。T细胞淋巴瘤起源于外周T细胞,其特征通常是T细胞受体(TCR)信号分子中的功能获得性基因变异。尽管这些致癌性改变被认为会驱动TCR通路诱导慢性增殖和细胞存活程序,但尚不清楚T细胞中是否含有能够抵消这些事件的肿瘤抑制因子。在这里,我们表明,在人类T细胞淋巴瘤小鼠模型中,淋巴细胞中致癌性TCR信号的急性增强会驱动这些细胞在体内强烈扩增。然而,这种反应是短暂的,并被细胞内在机制有力地抵消。随后使用T细胞特异性转座子诱变进行的全基因组体内筛选确定,编码抑制性受体程序性死亡-1(PD-1)的PDCD1是抑制致癌性T细胞信号的主基因。在人类T细胞淋巴瘤中也经常观察到PDCD1的单等位基因和双等位基因缺失,其频率可超过30%,表明具有高度的临床相关性。从机制上讲,PD-1的活性会提高肿瘤抑制因子PTEN的水平,并减弱癌前细胞中激酶AKT和PKC的信号传导。相比之下,PD-1的纯合或杂合缺失会使致癌刺激后T细胞不受限制地生长,并导致体内快速发展出高度侵袭性的淋巴瘤,这些淋巴瘤很容易移植给受体。因此,抑制性PD-1受体是T细胞淋巴瘤中一种有效的单倍体不足肿瘤抑制因子,在人类疾病中经常发生改变。这些发现将PD-1已知的生理功能扩展到抗原诱导的T细胞活化后预防免疫病理之外,对T细胞淋巴瘤治疗以及免疫肿瘤学更广泛背景下针对PD-1的当前策略具有启示意义。