促进乳腺癌免疫逃逸的“两面派”:Shc1
  • 酪氨酸激酶抑制剂(TKI)提高部分适应性免疫,酪氨酸激酶组的异质性和功能冗余是免疫应答持续的障碍;
  • Shc1 (ShcA)通路同时激活乳腺癌细胞内STAT3免疫抑制信号,破坏STAT1驱动的免疫监视,Y239/Y240-ShcA磷酸化受损,选择性降低STAT3活性,促进对免疫检查点抑制剂和肿瘤疫苗的敏感性;
  • TK信号的缺失启动STAT1驱动的免疫监视,代偿性STAT3过度活化可克服;
  • 抑制pY239/240-ShcA依赖性STAT3信号,增强乳腺癌对多种免疫治疗的敏感性。
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The Shc1 adaptor simultaneously balances Stat1 and Stat3 activity to promote breast cancer immune suppression

Shc1适配器同时平衡Stat1和tat3活性以促进乳腺癌免疫抑制

10.1038/ncomms14638

2017-03-09, Article

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Tyrosine kinase signalling within cancer cells is central to the establishment of an immunosuppressive microenvironment. Although tyrosine kinase inhibitors act, in part, to augment adaptive immunity, the increased heterogeneity and functional redundancy of the tyrosine kinome is a hurdle to achieving durable responses to immunotherapies. We previously identified the Shc1 (ShcA) scaffold, a central regulator of tyrosine kinase signalling, as essential for promoting breast cancer immune suppression. Herein we show that the ShcA pathway simultaneously activates STAT3 immunosuppressive signals and impairs STAT1-driven immune surveillance in breast cancer cells. Impaired Y239/Y240-ShcA phosphorylation selectively reduces STAT3 activation in breast tumours, profoundly sensitizing them to immune checkpoint inhibitors and tumour vaccines. Finally, the ability of diminished tyrosine kinase signalling to initiate STAT1-driven immune surveillance can be overcome by compensatory STAT3 hyperactivation in breast tumours. Our data indicate that inhibition of pY239/240-ShcA-dependent STAT3 signalling may represent an attractive therapeutic strategy to sensitize breast tumours to multiple immunotherapies.

First Authors:
Ryuhjin Ahn

Correspondence Authors:
Josie Ursini-Siegel

All Authors:
Ryuhjin Ahn,Valérie Sabourin,Alicia M Bolt,Steven Hébert,Stephanie Totten,Nicolas De Jay,Maria Carolina Festa,Yoon Kow Young,Young Kyuen Im,Tony Pawson,Antonis E Koromilas,William J Muller,Koren K Mann,Claudia L Kleinman,Josie Ursini-Siegel

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