Distinct roles of programmed death ligand 1 alternative splicing isoforms in colorectal cancer.
Distinct roles of programmed death ligand 1 alternative splicing isoforms in colorectal cancer.
复制标题
程序性死亡配体 1 选择性剪接亚型在结直肠癌中的独特作用。
DOI：
10.1111/cas.14690
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发表时间：
2021-01
期刊：
影响因子：
5.7
通讯作者：
Lai M
中科院分区：
文献类型：
--
作者：
Wang C;Weng M;Xia S;Zhang M;Chen C;Tang J;Huang D;Yu H;Sun W;Zhang H;Lai M
尽管抗程序性死亡- 1 (PD - 1)/程序性死亡配体- 1 （PD - L1）免疫疗法在某些癌症中取得了巨大的成功，但大多数结直肠癌（CRC）患者仍然没有反应。因此，需要进一步澄清潜在的机制，以改善治疗。在这项研究中，我们探索了不同PD‐L1选择性剪接异构体在CRC中的不同功能。我们研究了PD‐L1敲除/敲除细胞的生物学功能，并通过PD‐L1亚型a、b和c的过表达进行了验证。我们还分析了PD‐L1亚型在免疫监视抗性中的作用。同时，我们进行了RNA‐seq筛选PD‐L1亚型调控的下游分子。最后，我们检测了一组血清样本和两组结直肠癌组织样本中PD‐L1和PD‐L1亚型的水平，并分析了两例临床结直肠癌病例中PD‐L1亚型与PD‐1阻断治疗反应的相关性。结果表明，PD‐L1基因敲除抑制了T细胞的增殖、迁移和侵袭，并且b亚型对T细胞的抑制作用比其他两种亚型更显著。此外，异构体c可以通过调节上皮-间质转化来促进结直肠癌的进展。临床数据显示，PD‐L1阳性表达的结直肠癌患者的总生存期较差。血清PD‐L1水平高与预后不良相关。异构体b或c的水平与预后呈负相关，较高水平的异构体b与抗pd - 1治疗的良好反应相关。综上所述，b型异构体应被视为抗PD‐1/PD‐L1免疫治疗临床反应性的生物标志物；同种异构体c具有促进转移的作用，是CRC治疗的新潜在靶点。在本报告中，我们发现PD‐L1异构体b对T细胞的抑制作用比其他两种异构体更显著，它应该被视为对免疫检查点阻断治疗的临床反应的生物标志物。PD‐L1亚型c是一种前转移基因，通过调节上皮-间质转化促进结直肠癌的进展。它应被视为潜在的预后生物标志物和肿瘤治疗的有效靶点。此外，这些发现提出了PD‐L1选择性剪接可能成为结直肠癌免疫治疗的新靶点的可能性。
Although anti–programmed death‐1 (PD‐1)/programmed death ligand 1 (PD‐L1) immunotherapy has achieved great success in some cancers, most colorectal cancer (CRC) patients remain unresponsive. Therefore, further clarification of the underlying mechanisms is needed to improve the therapy. In this study, we explored the distinct functions of different PD‐L1 alternative splicing isoforms in CRC. We investigated the biological functions in PD‐L1 knocked down/knockout cells, which were verified through overexpression of PD‐L1 isoforms a, b, and c. The roles of PD‐L1 isoforms in immune surveillance resistance was also analyzed. Meanwhile, we performed RNA‐seq to screen the downstream molecules regulated by PD‐L1 isoforms. Finally, we detected PD‐L1 and PD‐L1 isoforms levels in a cohort of serum samples, two cohorts of CRC tissue samples, and analyzed the correlation of PD‐L1 isoforms with PD‐1 blockade therapy response in two clinical CRC cases. The results indicated that PD‐L1 knockout inhibited proliferation, migration, and invasion, and isoform b exerted a more significant inhibitory effect on T cells than the other two isoforms. Moreover, isoform c could promote CRC progression through regulating epithelial‐mesenchymal transition. Clinical data showed that CRC patients with positive PD‐L1 expression were associated with poorer overall survival. High serum PD‐L1 level was associated with poor prognosis. The level of isoform b or c was negatively associated with prognosis, and a higher level of isoform b was associated with a good response to anti–PD‐1 therapy. In conclusion, isoform b should be considered as a biomarker for clinical responsiveness to anti–PD‐1/PD‐L1 immunotherapy; isoform c had a prometastatic role and is a new potential target for CRC therapy. In this report, we found that PD‐L1 isoform b could exert a more significant inhibitory effect on T cells than the other two isoforms, and it should be considered as a biomarker of clinical response to immune checkpoint blockade therapy. PD‐L1 isoform c is a prometastatic gene that promotes colorectal cancer progression through regulating epithelial‐mesenchymal transition. It should be considered as a potential prognostic biomarker and an effective target for tumor therapy. Moreover, these findings raise the possibility that PD‐L1 alternative splicing might become a novel target for colorectal cancer immunotherapy.
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DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
DOI：
10.1056/nejmoa1510665
发表时间：
2015-11-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Motzer RJ;Escudier B;McDermott DF;George S;Hammers HJ;Srinivas S;Tykodi SS;Sosman JA;Procopio G;Plimack ER;Castellano D;Choueiri TK;Gurney H;Donskov F;Bono P;Wagstaff J;Gauler TC;Ueda T;Tomita Y;Schutz FA;Kollmannsberger C;Larkin J;Ravaud A;Simon JS;Xu LA;Waxman IM;Sharma P;CheckMate 025 Investigators
通讯作者：
CheckMate 025 Investigators
DOI：
10.1084/jem.20090847
发表时间：
2009-12-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Francisco LM;Salinas VH;Brown KE;Vanguri VK;Freeman GJ;Kuchroo VK;Sharpe AH
通讯作者：
Sharpe AH
影响因子：
82.9
作者：
Cerezo, Michael;Guemiri, Ramdane;Robert, Caroline
通讯作者：
Robert, Caroline
影响因子：
32.4
作者：
Butte, Manish J.;Keir, Mary E.;Freeman, Gordon J.
通讯作者：
Freeman, Gordon J.