The Shc1 Scaffold protein simultaneously balances Stat1 and Stat3 activity in breast cancer to promote immune suppression and resistance to immunotherapy.. Mus musculus strain:FVB/N

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.