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The Shc1 adaptor simultaneously balances Stat1 and Stat3 activity to promote breast cancer immune suppression
Ryuhjin Ahn1,2, Valérie Sabourin1, Alicia M Bolt1,3
1Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.
Abstract:
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.
Insights
Targeting the Shc1 (ShcA) scaffold pathway in breast cancer can overcome immune suppression. Inhibiting specific ShcA phosphorylation sensitizes tumors to immunotherapies by modulating STAT3 and STAT1 signals.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Tyrosine kinase signaling in cancer cells creates an immunosuppressive tumor microenvironment.
- Tyrosine kinase inhibitors can enhance adaptive immunity but face challenges due to kinome complexity.
- The Shc1 (ShcA) scaffold is crucial for breast cancer immune suppression.
Purpose of the Study:
- To investigate the role of the ShcA pathway in regulating immune signals within breast cancer.
- To determine if modulating ShcA phosphorylation can enhance anti-tumor immunity and response to immunotherapy.
Main Methods:
- Analysis of ShcA signaling in breast cancer cells.
- Assessment of STAT3 and STAT1 activation in response to ShcA pathway modulation.
- Evaluation of tumor response to immunotherapies following targeted ShcA inhibition.
Main Results:
- The ShcA pathway activates immunosuppressive STAT3 signals and inhibits immune-surveillance STAT1 signals.
- Reduced Y239/Y240-ShcA phosphorylation selectively decreases STAT3 activation in breast tumors.
- This impairment sensitizes tumors to immune checkpoint inhibitors and vaccines.
- Compensatory STAT3 hyperactivation can override diminished tyrosine kinase signaling-induced STAT1 immune surveillance.
Conclusions:
- Targeting pY239/240-ShcA-dependent STAT3 signaling is a potential therapeutic strategy.
- This approach may sensitize breast tumors to various immunotherapies, including immune checkpoint inhibitors and vaccines.
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