The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma
The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma
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DOI：
10.1158/0008-5472.can-19-3993
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发表时间：
2020-10-15
期刊：
影响因子：
11.2
通讯作者：
Saya, Hideyuki
中科院分区：
文献类型：
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作者：
Sugihara, Eiji;Hashimoto, Norisato;Saya, Hideyuki
死亡受体Fas介导的细胞凋亡不仅消除非特异性和自身反应性的B细胞，而且在抗肿瘤免疫中发挥重要作用。然而，在淋巴瘤发生过程中Fas介导的细胞凋亡诱导受损的可能机制仍不清楚。在这项研究中，我们采用我们开发的同基因淋巴瘤模型，以证明Fas的下调是淋巴瘤的发展和淋巴瘤细胞的生存，以逃避免疫细胞毒性。在小鼠和人淋巴瘤细胞中，CD 40信号激活显著恢复Fas表达，从而诱导Fas配体处理后的细胞凋亡。然而，发现某些人淋巴瘤细胞系对Fas介导的细胞凋亡具有抗性，Livin（黑色素瘤细胞凋亡抑制蛋白; ML-IAP）被鉴定为这种抗性的驱动因素。Livin高表达和Fas低表达与侵袭性非霍奇金淋巴瘤预后不良有关。Livin的表达由溴结构域和末端外（BET）蛋白BRD 4和BRD 2紧密驱动，表明Livin的表达在难治性淋巴瘤细胞中受到表观遗传学调节以保护它们免受Fas介导的凋亡。因此，结合CD 40介导的Fas恢复与靶向的BET蛋白Livin轴可能作为一个有前途的免疫策略难治性B细胞lymphoma.Significance：这些研究结果产生的见解，确定难治性淋巴瘤的危险因素，并提供了一个有前途的治疗肿瘤耐Fas介导的抗肿瘤免疫。
Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins-Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma.Significance: These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity.