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

The Journal of Clinical Investigation
Rebecca L VartuliHeide L Ford

Abstract

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 E...Continue Reading

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Citations

Jul 31, 2020·Critical Reviews in Biochemistry and Molecular Biology·Rashmi S HegdeRam Naresh Pandey
Oct 14, 2019·European Journal of Cancer : Official Journal for European Organization for Research and Treatment of Cancer (EORTC) [and] European Association for Cancer Research (EACR)·Amal Kamal Abdel-AzizSaverio Minucci
Feb 9, 2021·Technology in Cancer Research & Treatment·Wentao LiuMaokai Wang
Aug 17, 2021·Frontiers in Cell and Developmental Biology·Shengxian XuHongtuan Zhang
Sep 12, 2021·Nature Reviews. Clinical Oncology·Renumathy DhanasekaranDean W Felsher
Oct 8, 2021·The Journal of Experimental Medicine·Guoxin ZhangJeremy N Rich
Nov 12, 2021·Protein Science : a Publication of the Protein Society·Jothi AnantharajanCongBao Kang
Jul 2, 2021·Biochemical Society Transactions·Upendra Kumar SoniRashmi S Hegde

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Methods Mentioned

BETA
reverse transcription PCR
flow cytometry
dissection

Software Mentioned

Cibersort
R

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