title: Murine pancreatic adenocarcinoma reduces Ikaros expression and disrupts T cell homeostasis.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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
  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.
authors: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America.
authors: Nadine
authors: N
authors: Nelson
authors: Department of Pathology and Cell Biology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America.
authors: Shengyan
authors: S
authors: Xiang
authors: Department of Pathology and Cell Biology, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America.
authors: Xiaohong
authors: X
authors: Zhang
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors: Danielle
authors: D
authors: Gilvary
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors: Julie
authors: J
authors: Djeu
authors: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors: Kazim
authors: K
authors: Husain
authors: Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors: Mokenge
authors: M
authors: Malafa
authors: Department of Surgery, Brody School of Medicine, East Carolina University, Greenville, NC, United States of America.
authors: Nasreen
authors: N
authors: Vohra
authors: Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors: Shari
authors: S
authors: Pilon-Thomas
authors: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, United States of America; Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL, United States of America.
authors: Tomar
authors: T
authors: Ghansah
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D017252:CD3 Complex / Q000378:metabolism; D047390:Casein Kinase II / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006706:Homeostasis / Q000235:genetics*; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D017252:CD3 Complex; D017476:Receptors, Neuropeptide Y; D025801:Ubiquitin; D051740:Ikaros Transcription Factor; C109491:neuropeptide Y4 receptor; D047390:Casein Kinase II; D046988:Proteasome Endopeptidase Complex
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