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dc.contributor.advisorFord, Heide
dc.contributor.authorVartuli, Rebecca
dc.contributor.committeememberReyland, Mary
dc.contributor.committeememberSlansky, Jill
dc.contributor.committeememberDeGregori, James
dc.contributor.committeememberKedl, Ross
dc.contributor.committeememberZhao, Rui
dc.contributor.committeememberNemenoff, Raphael
dc.date.accessioned2018-01-16T18:04:15Z
dc.date.available2018-07-12T18:04:21Z
dc.date.submitted2017
dc.descriptionIncludes bibliographical references.
dc.descriptionFall
dc.description.abstractThe Eya family of proteins are critical developmental transcription factors that are highly expressed in early embryogenesis where they promote cell survival, proliferation, migration and invasion. Most Eya proteins are downregulated after development is complete, but amplification and/or re-expression of Eya proteins occurs in many tumor types. In breast cancer, the Eya proteins regulate tumorigenesis and metastasis through their ability to act as transcriptional cofactors to the Six family of proteins and to act as tyrosine phosphatases. Intriguingly, Eya proteins contain a completely separate domain that contains threonine phosphatase activity, and this activity was recently implicated in innate immune responses in fibroblasts and in Drosophila. However, whether the Eya proteins alter immune detection of tumors is unknown. Here we describe a completely novel role for Eya3, which is upregulated in triple negative breast cancers, in mediating tumor associated immune suppression. We demonstrate for the first time that Eya3 loss dramatically decreases tumor growth in immune competent mice, without altering proliferation. Our data show that Eya3 leads to decreases in the infiltration of cytotoxic CD8+ T cells into mammary carcinoma tumors, and to T cell exhaustion. Depletion of CD8+ T cells demonstrates that they are required for Eya3-mediated tumor growth. Mechanistically, we find that Eya3, via its Thr phosphatase activity, upregulates PD-L1 expression on mammary carcinoma cells, and rescue of PD-L1 in Eya3 KD restores tumor growth and progression. Finally, we demonstrate that human breast tumors expressing Eya3 have a decreased CD8+ T cell signature, providing evidence that this pathway is maintained in the human setting. Our data uncover a completely novel role for Eya3 in mediating tumor-associated immune suppression, and suggest its utility as a biomarker or target that can be leveraged to enhance checkpoint therapies.
dc.identifierVartuli_ucdenveramc_1639D_10472.pdf
dc.identifier.urihttps://hdl.handle.net/10968/2184
dc.languageEnglish
dc.publisherUniversity of Colorado Anschutz Medical Campus. Strauss Health Sciences Library
dc.rightsCopyright of the original work is retained by the author.
dc.rights.accessEmbargo Expires: 07/12/2018
dc.subject.meshPhosphoprotein Phosphatases
dc.subject.meshBreast Neoplasms
dc.titleEya3 threonine phosphatase promotes triple negative breast cancer growth through PD-L1 regulation of the tumor adaptive immune response, The
dc.typeThesis
dcterms.embargo.expires2018-07-12
thesis.degree.disciplineMolecular Biology
thesis.degree.grantorUniversity of Colorado at Denver, Anschutz Medical Campus
thesis.degree.levelDoctoral
thesis.degree.nameDoctor of Philosophy (Ph.D.)


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