Eya3 promotes breast tumor-associated immune suppression via threonine phosphatase-mediated PD-L1 upregulation

J Clin Invest. 2018 Jun 1;128(6):2535-2550. doi: 10.1172/JCI96784. Epub 2018 May 14.


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-associated 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.

Keywords: Breast cancer; Immunology; Oncology; T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Female
  • Gene Expression Regulation, Neoplastic / immunology*
  • Humans
  • Immunosuppression Therapy*
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / immunology*
  • Protein Tyrosine Phosphatases / genetics
  • Protein Tyrosine Phosphatases / immunology*
  • Transcriptional Activation / immunology*
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / immunology*
  • Triple Negative Breast Neoplasms / pathology
  • Up-Regulation / immunology*


  • B7-H1 Antigen
  • CD274 protein, human
  • DNA-Binding Proteins
  • Neoplasm Proteins
  • EYA3 protein, human
  • Protein Tyrosine Phosphatases