The Shc1 adaptor simultaneously balances Stat1 and Stat3 activity to promote breast cancer immune suppression

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 and Josie Ursini-Siegel ()
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Ryuhjin Ahn: Lady Davis Institute for Medical Research
Valérie Sabourin: Lady Davis Institute for Medical Research
Alicia M. Bolt: Lady Davis Institute for Medical Research
Steven Hébert: Lady Davis Institute for Medical Research
Stephanie Totten: Lady Davis Institute for Medical Research
Nicolas De Jay: Lady Davis Institute for Medical Research
Maria Carolina Festa: Lady Davis Institute for Medical Research
Yoon Kow Young: Lady Davis Institute for Medical Research
Young Kyuen Im: Lady Davis Institute for Medical Research
Tony Pawson: The Lunenfeld-Tanenbaum Research Institute, Sinai Health System
Antonis E. Koromilas: Lady Davis Institute for Medical Research
William J. Muller: Lady Davis Institute for Medical Research
Koren K. Mann: Lady Davis Institute for Medical Research
Claudia L. Kleinman: Lady Davis Institute for Medical Research
Josie Ursini-Siegel: Lady Davis Institute for Medical Research

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14638

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