Murine Pancreatic Adenocarcinoma Reduces Ikaros Expression and Disrupts T Cell Homeostasis

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dc.contributor.authorNelson, Nadine
dc.contributor.authorXiang, Shengyan
dc.contributor.authorZhang, Xiaohong
dc.contributor.authorGilvary, Danielle
dc.contributor.authorDjeu, Julie
dc.contributor.authorHusain, Kazim
dc.contributor.authorMalafa, Mokenge
dc.contributor.authorVohra, Nasreen
dc.contributor.authorPilon-Thomas, Shari
dc.contributor.authorGhansah, Tomar
dc.date.accessioned2016-07-28T18:24:14Z
dc.date.available2016-07-28T18:24:14Z
dc.date.issued2015-01
dc.description.abstractBackground Maintenance of T cell immune homeostasis is critical for adequate anti-tumor immunity. The transcription factor Ikaros is essential for lymphocyte development including T cells. Alterations in Ikaros expression occur in blood malignancies in humans and mice. In this study, we investigated the role of Ikaros in regulating T cell immune balance in pancreatic cancer mouse models. Methodology and Principal Findings Using our Panc02 tumor-bearing (TB) mouse model, western blot analysis revealed a reduction in Ikaros proteins while qRT-PCR showed no differences in Ikaros mRNA levels in TB splenocytes compared to control. Treatment of naïve splenocytes with the proteasomal inhibitor, MG132, stabilized Ikaros expression and prevented Ikaros downregulation by Panc02 cells, in vitro. Western blot analyses showed a reduction in protein phosphatase 1 (PP1) and protein kinase CK2 expression in TB splenocytes while CK2 activity was increased. Immunofluorescence microscopy revealed altered punctate staining of Ikaros in TB splenocytes. Flow cytometry revealed a significant decrease in effector CD4+ and CD8+ T cell percentages but increased CD4+CD25+ regulatory T cells in TB splenocytes. Similar alterations in T cell percentages, as well as reduced Ikaros and CK2 but not PP1 expression, were observed in a transgenic, triple mutant (TrM) pancreatic cancer model. Ikaros expression was also reduced in enriched TB CD3+ T cells. MG132 treatment of naïve CD3+ T cells stabilized Ikaros expression in the presence of Panc02 cells. Western blots showed reduced PP1 and CK2 expression in TB CD3+ T cells. Conclusions/Significance The results of this study suggest that the pancreatic tumor microenvironment may cause proteasomal degradation of Ikaros, possibly via dysregulation of PP1 and CK2 expression and activity, respectively. This loss of Ikaros expression may contribute to an imbalance in T cell percentages. Ikaros may potentially be a therapeutic target to restore T cell homeostasis in pancreatic cancer hosts, which may be critical for effective anti-tumor immunity.en_US
dc.identifier.citationPLoS ONE; 10:1 p. 1-15en_US
dc.identifier.doi10.1371/journal.pone.0115546
dc.identifier.issn1932-6203
dc.identifier.pmidpmc4309586en_US
dc.identifier.urihttp://hdl.handle.net/10342/5859
dc.relation.urihttp://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0115546en_US
dc.subjectT cellsen_US
dc.subjectPancreatic canceren_US
dc.subjectMouse modelsen_US
dc.subjectRegulatory T cellsen_US
dc.subjectHomeostasisen_US
dc.titleMurine Pancreatic Adenocarcinoma Reduces Ikaros Expression and Disrupts T Cell Homeostasisen_US
dc.typeArticleen_US
ecu.journal.issue1en_US
ecu.journal.namePLoS ONEen_US
ecu.journal.pages1-15en_US
ecu.journal.volume10en_US

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