PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity
PDL1 Signals through Conserved Sequence Motifs to Overcome Interferon-Mediated Cytotoxicity
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DOI：
10.1016/j.celrep.2017.07.075
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发表时间：
2017-08-22
期刊：
影响因子：
8.8
通讯作者：
Escors, David
中科院分区：
文献类型：
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作者：
Gato-Canas, Maria;Zuazo, Miren;Escors, David
PDL 1阻断产生显著的临床应答，认为通过防止PDL 1-PD 1 T细胞抑制性相互作用而通过T细胞再活化而发生。在这里，我们发现PDL 1细胞内在信号可以保护癌细胞免受干扰素（IFN）的细胞毒性，并加速肿瘤进展。PDL 1通过一类保守的序列基序抑制IFN信号转导，这些序列基序介导与IFN信号转导的串扰。PDL 1表达的消除或抗体介导的PDL 1阻断通过STAT 3/半胱天冬酶-7依赖性途径强烈地使癌细胞对IFN细胞毒性敏感。此外，在这些PDL 1序列基序中发现的人癌中的体细胞突变破坏了基序调控，导致PDL 1分子具有增强的I型和II型IFN细胞毒性的保护活性。总体而言，我们的研究结果揭示了PDL 1在癌细胞中作为对抗IFN细胞毒性的第一道防线的作用模式。
PDL1 blockade produces remarkable clinical responses, thought to occur by T cell reactivation through prevention of PDL1-PD1 T cell inhibitory interactions. Here, we find that PDL1 cell-intrinsic signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression. PDL1 inhibited IFN signal transduction through a conserved class of sequence motifs that mediate crosstalk with IFN signaling. Abrogation of PDL1 expression or antibody-mediated PDL1 blockade strongly sensitized cancer cells to IFN cytotoxicity through a STAT3/caspase-7-dependent pathway. Moreover, somatic mutations found in human carcinomas within these PDL1 sequence motifs disrupted motif regulation, resulting in PDL1 molecules with enhanced protective activities from type I and type II IFN cytotoxicity. Overall, our results reveal a mode of action of PDL1 in cancer cells as a first line of defense against IFN cytotoxicity.