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

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

doi:10.1038/ncomms14638

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.

Highlights

Tyrosine kinase signalling within cancer cells is central to the establishment of an immunosuppressive microenvironment
We show that the ShcA phosphotyrosine motifs potentiate immune suppression by limiting signal transducer and activator of transcription (STAT)-1-driven anti-tumour immunity, while simultaneously increasing STAT3 immunosuppressive signals
Our studies provide the first evidence that perturbing ShcA signalling has the potential to modulate immune responsiveness by altering the balance between STAT1-driven immune surveillance and STAT1/STAT3-driven immune suppression

Summary

Introduction

Tyrosine kinase signalling within cancer cells is central to the establishment of an immunosuppressive microenvironment. Diverse immunotherapies are in clinical trials including the following: (1) vaccines, which stimulate immune responses against tumour antigens; (2) monoclonal antibodies, which promote immune-mediated cytotoxicity; and (3) oncolytic viruses and (4) immune checkpoint inhibitors, which overcome T-cell anergy[1]. These therapeutic approaches have significantly improved patient outcome in metastatic melanoma and nonsmall cell lung cancer[2,3]. We show that the ShcA phosphotyrosine motifs potentiate immune suppression by limiting signal transducer and activator of transcription (STAT)-1-driven anti-tumour immunity, while simultaneously increasing STAT3 immunosuppressive signals. We further demonstrate that attenuating ShcA signalling downstream of activated tyrosine kinases sensitizes mammary tumours to several immunotherapies

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Results

Conclusion