Rho-associated protein kinase-dependent moesin phosphorylation is required for PD-L1 stabilization in breast cancer.
Rho-associated protein kinase-dependent moesin phosphorylation is required for PD-L1 stabilization in breast cancer.
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DOI：
10.1002/1878-0261.12804
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发表时间：
2020-11
影响因子：
6.6
通讯作者：
Xu B
中科院分区：
文献类型：
--
作者：
Meng F;Su Y;Xu B
在这里，我们证明了由Rho相关蛋白激酶（ROCK）磷酸化的moesin （MSN）通过阻断SPOP介导的PD‐L1降解来稳定PD‐L1蛋白水平。ROCK抑制剂Y‐27632应用于乳腺肿瘤免疫活性小鼠，可抑制肿瘤进展并触发抗肿瘤T细胞活性。程序性细胞死亡配体（PD‐L1）的表达与乳腺癌预后不良有关。了解PD‐L1在乳腺癌中的表达调控可以为乳腺癌的治疗提供新的策略。在这里，我们证明了通过Rho相关蛋白激酶（ROCK）磷酸化moesin （MSN）可以稳定PD‐L1蛋白水平。我们的研究结果表明，磷酸化的MSN可能与E3泛素连接酶SPOP竞争结合PD‐L1。通过Y‐27632抑制剂或MSN沉默抑制ROCK降低PD‐L1表达，导致体内和体外T细胞活化。将Y‐27632注入乳腺肿瘤免疫活性Balb/c小鼠体内，可抑制肿瘤进展，增强CD4+和CD8+ T细胞浸润。Y - 27632治疗小鼠肿瘤的RNA - seq分析显示，ROCK抑制上调了几个免疫应答基因。然而，Y‐27632和抗PD‐1抗体的结合并没有显示出由于Y‐27632存在时PD‐L1减少而产生的加性或协同效应。我们的研究揭示了通过ROCK - MSN途径调控PD - L1的一个以前未被认识的机制。此外，我们发现ROCK抑制剂可以与乳腺癌免疫治疗联合使用。
Here, we demonstrate that moesin (MSN) phosphorylation by Rho‐associated protein kinase (ROCK) stabilizes PD‐L1 protein levels by blocking SPOP mediating PD‐L1 degradation. Administration of ROCK inhibitor Y‐27632 into immunocompetent mice bearing breast tumors suppressed tumor progression and triggers antitumor T‐cell activity. Expression of programmed cell death ligand (PD‐L1) is associated with poor prognosis in breast cancer. Understanding the regulation of PD‐L1 expression in breast cancer could provide a new strategy for breast cancer treatment. Here, we demonstrate that moesin (MSN) phosphorylation by Rho‐associated protein kinase (ROCK) stabilizes PD‐L1 protein levels. Our results indicate that phosphorylated MSN may compete with the E3 ubiquitin ligase SPOP for binding PD‐L1. ROCK inhibition via the Y‐27632 inhibitor or MSN silencing decreased PD‐L1 expression, resulting in T‐cell activation both in vitro and in vivo. Administration of Y‐27632 into immunocompetent Balb/c mice bearing breast tumors suppressed tumor progression and enhanced CD4+ and CD8+ T‐cell infiltration. RNA‐seq analysis of Y‐27632‐treated mouse tumors revealed that ROCK inhibition upregulated several immune response genes. However, the combination of Y‐27632 and an anti‐PD‐1 antibody did not show additive or synergistic effects due to reduced PD‐L1 in the presence of Y‐27632. Our study unravels a previously unappreciated mechanism of PD‐L1 regulation through the ROCK‐MSN pathway. Moreover, we found that ROCK inhibitors could be combined with breast cancer immunotherapy.
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影响因子：
10.3
作者：
Borin TF;Arbab AS;Gelaleti GB;Ferreira LC;Moschetta MG;Jardim-Perassi BV;Iskander AS;Varma NR;Shankar A;Coimbra VB;Fabri VA;de Oliveira JG;Zuccari DA
通讯作者：
Zuccari DA
DOI：
10.1158/1078-0432.ccr-16-3215
发表时间：
2017-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jiao S;Xia W;Yamaguchi H;Wei Y;Chen MK;Hsu JM;Hsu JL;Yu WH;Du Y;Lee HH;Li CW;Chou CK;Lim SO;Chang SS;Litton J;Arun B;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
PD-1检查点途径的分子和生化方面。
DOI：
10.1056/nejmra1514296
发表时间：
2016-11-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Boussiotis VA
通讯作者：
Boussiotis VA
影响因子：
64.8
作者：
Burr ML;Sparbier CE;Chan YC;Williamson JC;Woods K;Beavis PA;Lam EYN;Henderson MA;Bell CC;Stolzenburg S;Gilan O;Bloor S;Noori T;Morgens DW;Bassik MC;Neeson PJ;Behren A;Darcy PK;Dawson SJ;Voskoboinik I;Trapani JA;Cebon J;Lehner PJ;Dawson MA
通讯作者：
Dawson MA
影响因子：
158.5
作者：
Schmid, P.;Adams, S.;Emens, L. A.
通讯作者：
Emens, L. A.