%0 Journal Article
%T Eya3 promotes breast tumor¨Cassociated immune suppression via threonine phosphatase¨Cmediated PD-L1 upregulation
%A Debashis Ghosh
%A Heide L. Ford
%A Hengbo Zhou
%A James C. Costello
%A Jared Klarquist
%A Jill E. Slansky
%A Lingdi Zhang
%A Melanie Y. Vincent
%A Pratyaydipta Rudra
%A Rani K. Powers
%A Rebecca L. Vartuli
%A Ross M. Kedl
%A Rui Zhao
%J The Journal of Clinical Investigation
%D 2018
%R 10.1172/JCI96784
%X Eya proteins are critical developmental regulators that are highly expressed in embryogenesis but downregulated after development. Amplification and/or re-expression of Eyas occurs in many tumor types. In breast cancer, Eyas regulate tumor progression by acting as transcriptional cofactors and tyrosine phosphatases. Intriguingly, Eyas harbor a separate threonine (Thr) phosphatase activity, which was previously implicated in innate immunity. Here we describe what we believe to be a novel role for Eya3 in mediating triple-negative breast cancer¨Cassociated immune suppression. Eya3 loss decreases tumor growth in immune-competent mice and is associated with increased numbers of infiltrated CD8+ T cells, which, when depleted, reverse the effects of Eya3 knockdown. Mechanistically, Eya3 utilizes its Thr phosphatase activity to dephosphorylate Myc at pT58, resulting in a stabilized form. We show that Myc is required for Eya3-mediated increases in PD-L1, and that rescue of PD-L1 in Eya3-knockdown cells restores tumor progression. Finally, we demonstrate that Eya3 significantly correlates with PD-L1 in human breast tumors, and that tumors expressing high levels of Eya3 have a decreased CD8+ T cell signature. Our data uncover a role for Eya3 in mediating tumor-associated immune suppression, and suggest that its inhibition may enhance checkpoint therapies
%U https://www.jci.org/articles/view/96784