The Shc1 Scaffold protein simultaneously balances Stat1 and Stat3 activity in breast cancer to promote immune suppression and resistance to immunotherapy.

Receptor and cytoplasmic tyrosine kinases are key signal integrators in poor outcome breast cancers that are central to the establishment of an immunosuppressive microenvironment. Immunotherapies represent an emerging approach within the armament of anti-cancer agents. Although the efficacy of tyrosine kinase inhibitors relies, in part, on their ability to augment adaptive immunity, the increased heterogeneity and functional redundancy of the tyrosine kinome in poor outcome breast cancers represents a significant hurdle to achieving durable responses to immunotherapies. We previously identified the Shc1 (ShcA) scaffold protein, a central regulator of tyrosine kinase signaling, as essential for promoting immune suppression. Here we show that the ShcA pathway simultaneously activates STAT3 immunosuppressive signals and impairs STAT1-driven immune surveillance in breast cancer cells. Impaired phosphorylation of Y239/Y240 residues on ShcA potently and selectively reduces STAT3 activation in breast tumors, profoundly sensitizing them to immune checkpoint inhibitors and tumor vaccines. Finally, the ability of diminished tyrosine kinase signaling to initiate STAT1-driven immune surveillance in breast tumors can be overcome by a compensatory hyper-activation of STAT3. Our data indicates the development of pharmacological inhibitors that prevent pY239/240-ShcA dependent STAT3 signaling may represent an attractive therapeutic strategy to sensitize breast tumors to multiple immunotherapies.

受体型与胞质型酪氨酸激酶（receptor and cytoplasmic tyrosine kinases）是预后不良乳腺癌中的关键信号整合分子，其在免疫抑制微环境的构建中发挥核心作用。免疫治疗是抗肿瘤药物武器库中新兴的治疗手段。尽管酪氨酸激酶抑制剂（tyrosine kinase inhibitors）的疗效部分依赖于其增强适应性免疫的能力，但预后不良乳腺癌中酪氨酸激酶组（tyrosine kinome）的异质性升高与功能冗余现象，成为实现免疫治疗持久应答的重大障碍。我们先前鉴定出Shc1（ShcA）支架蛋白（scaffold protein）——酪氨酸激酶信号通路的核心调控因子——是促进免疫抑制的必需分子。本研究证实，ShcA通路可同时激活信号转导与转录激活因子3（STAT3）介导的免疫抑制信号，并削弱乳腺癌细胞中信号转导与转录激活因子1（STAT1）驱动的免疫监视功能。ShcA蛋白上Y239/Y240位点的磷酸化缺陷，可强效且选择性地降低乳腺肿瘤中STAT3的激活水平，显著增强肿瘤对免疫检查点抑制剂（immune checkpoint inhibitors）与肿瘤疫苗的敏感性。最后，减弱的酪氨酸激酶信号通路启动乳腺肿瘤中STAT1介导的免疫监视的能力，可通过STAT3的代偿性过度激活予以抵消。本研究数据表明，开发能够阻断pY239/240-ShcA依赖性STAT3信号通路的药理学抑制剂，或可成为一种极具前景的治疗策略，以增强乳腺肿瘤对多种免疫治疗的敏感性。