EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance.
EZH2 inhibition remodels the inflammatory senescence-associated secretory phenotype to potentiate pancreatic cancer immune surveillance.
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EZH2抑制重塑了炎症性衰老相关的分泌表型，以增强胰腺癌免疫监测。
DOI：
10.1038/s43018-023-00553-8
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发表时间：
2023-06
期刊：
影响因子：
22.7
通讯作者：
Ruscetti, Marcus
中科院分区：
文献类型：
--
作者：
Chibaya, Loretah;Murphy, Katherine C. C.;DeMarco, Kelly D. D.;Gopalan, Sneha;Liu, Haibo;Parikh, Chaitanya N. N.;Lopez-Diaz, Yvette;Faulkner, Melissa;Li, Junhui;Morris, John P. P.;Ho, Yu-jui;Chana, Sachliv K. K.;Simon, Janelle;Luan, Wei;Kulick, Amanda;de Stanchina, Elisa;Simin, Karl;Zhu, Lihua Julie;Fazzio, Thomas G. G.;Lowe, Scott W. W.;Ruscetti, Marcus
在某些恶性肿瘤中产生持久应答的免疫疗法在胰腺导管腺癌（PDAC）中失败，这是由于猖獗的免疫抑制和较差的肿瘤免疫原性。我们和其他人已经证明，诱导衰老相关分泌表型（SASP）可以是激活抗肿瘤自然杀伤细胞（NK）和T细胞免疫的有效方法。在这里，我们发现胰腺肿瘤微环境（TME）通过EZH 2介导的促炎SASP基因的表观遗传抑制抑制治疗诱导衰老后的NK和T细胞监视。EZH 2阻断刺激SASP趋化因子CCL 2和CXCL 9/10的产生，导致小鼠模型中NK和T细胞浸润和PDAC根除增强。EZH 2活性还与趋化因子信号传导和细胞毒性淋巴细胞的抑制以及PDAC患者存活率的降低相关。这些结果表明，EZH 2抑制促炎SASP，并且EZH 2抑制与衰老诱导疗法组合可能是在PDAC中实现免疫介导的肿瘤控制的有力手段。
Immunotherapies that produce durable responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of the senescence-associated secretory phenotype (SASP) can be an effective approach to activate anti-tumor Natural Killer (NK) and T cell immunity. Here we found the pancreas tumor microenvironment (TME) suppresses NK and T cell surveillance following therapy-induced senescence through EZH2-mediated epigenetic repression of pro-inflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK and T cell infiltration and PDAC eradication in mouse models. EZH2 activity was also associated with suppression of chemokine signaling and cytotoxic lymphocytes and reduced survival in PDAC patients. These results demonstrate that EZH2 represses of the pro-inflammatory SASP, and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC.
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影响因子：
12.4
作者：
Haas, Andrew R.;Tanyi, Janos L.;Beatty, Gregory L.
通讯作者：
Beatty, Gregory L.
DOI：
10.1084/jem.20130783
发表时间：
2013-09-23
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Iannello A;Thompson TW;Ardolino M;Lowe SW;Raulet DH
通讯作者：
Raulet DH
影响因子：
28.2
作者：
Cózar B;Greppi M;Carpentier S;Narni-Mancinelli E;Chiossone L;Vivier E
通讯作者：
Vivier E
影响因子：
16.6
作者：
Hamarsheh S;Groß O;Brummer T;Zeiser R
通讯作者：
Zeiser R
影响因子：
14.5
作者：
Chibaya, Loretah;Snyder, Jarin;Ruscetti, Marcus
通讯作者：
Ruscetti, Marcus