title: The Shc1 adaptor simultaneously balances Stat1 and Stat3 activity to promote breast cancer immune suppression.
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.
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, 845 Rue Sherbrooke O, Montréal, Quebec, Canada H3A 0G4.
authors.forename: Ryuhjin
authors.initials: R
authors.lastname: Ahn
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.
authors.forename: Valérie
authors.initials: V
authors.lastname: Sabourin
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.|Department of Oncology, McGill University, 546 Pine Avenue West, Montréal, Quebec, Canada H2W 1S6.
authors.forename: Alicia M
authors.initials: AM
authors.lastname: Bolt
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.
authors.forename: Steven
authors.initials: S
authors.lastname: Hébert
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, 845 Rue Sherbrooke O, Montréal, Quebec, Canada H3A 0G4.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Totten
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.|Department of Human Genetics, McGill University, 1205 Dr. Penfield Ave, Montréal, Quebec, Canada H3A 1B1.
authors.forename: Nicolas
authors.initials: N
authors.lastname: De Jay
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.
authors.forename: Maria Carolina
authors.initials: MC
authors.lastname: Festa
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.
authors.forename: Yoon Kow
authors.initials: YK
authors.lastname: Young
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, 845 Rue Sherbrooke O, Montréal, Quebec, Canada H3A 0G4.
authors.forename: Young Kyuen
authors.initials: YK
authors.lastname: Im
authors.affiliation: The Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 600 University Ave., Toronto, Ontario, Canada M5G 1X5.
authors.forename: Tony
authors.initials: T
authors.lastname: Pawson
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, 845 Rue Sherbrooke O, Montréal, Quebec, Canada H3A 0G4.|Department of Oncology, McGill University, 546 Pine Avenue West, Montréal, Quebec, Canada H2W 1S6.
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, 845 Rue Sherbrooke O, Montréal, Quebec, Canada H3A 0G4.|Department of Biochemistry, McGill University, McIntyre Medical Centre, Montréal, Quebec, Canada H3G 1Y6.|Goodman Cancer Research Centre, 1160 Avenue des Pins, Montréal, Quebec, Canada H3A 1A3.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, 845 Rue Sherbrooke O, Montréal, Quebec, Canada H3A 0G4.|Department of Oncology, McGill University, 546 Pine Avenue West, Montréal, Quebec, Canada H2W 1S6.
authors.forename: Koren K
authors.initials: KK
authors.lastname: Mann
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.|Department of Human Genetics, McGill University, 1205 Dr. Penfield Ave, Montréal, Quebec, Canada H3A 1B1.
authors.forename: Claudia L
authors.initials: CL
authors.lastname: Kleinman
authors.affiliation: Lady Davis Institute for Medical Research, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, Quebec, Canada H3T 1E2.|Department of Experimental Medicine, McGill University, 845 Rue Sherbrooke O, Montréal, Quebec, Canada H3A 0G4.|Department of Oncology, McGill University, 546 Pine Avenue West, Montréal, Quebec, Canada H2W 1S6.|Department of Biochemistry, McGill University, McIntyre Medical Centre, Montréal, Quebec, Canada H3G 1Y6.|Goodman Cancer Research Centre, 1160 Avenue des Pins, Montréal, Quebec, Canada H3A 1A3.
authors.forename: Josie
authors.initials: J
authors.lastname: Ursini-Siegel
mesh_terms: D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D019295:Computational Biology; D061025:Costimulatory and Inhibitory T-Cell Receptors / Q000037:antagonists & inhibitors / Q000276:immunology; D066264:Datasets as Topic; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D007157:Immunologic Surveillance; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology*; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D050794:STAT1 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000276:immunology* / Q000378:metabolism; D017423:Sequence Analysis, RNA; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000074322:Antineoplastic Agents, Immunological; D019496:Cancer Vaccines; D061025:Costimulatory and Inhibitory T-Cell Receptors; C000611649:IFNG protein, mouse; C528024:SHC1 protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D007371:Interferon-gamma