title: Expression of Sirt1 and FoxP3 in classical Hodgkin lymphoma and tumor infiltrating lymphocytes: Implications for immune dysregulation, prognosis and potential therapeutic targeting.
abstract: BACKGROUND
  Hodgkin Reed-Sternberg (HRS) cells may promote differentiation of CD4+ naïve T cells toward both FoxP3+ T regulatory (Treg) cells and TIA-1+ cytotoxic T lymphocytes (CTL). Previous studies suggest that an overabundance of cytotoxic TIA-1+ cells in relation to FoxP3+ T reg cells portends unfavorable outcomes in classical Hodgkin lymphoma (cHL), raising the possibility that its pathogenesis may be related to immune dysregulation. Sirt1 deacetylates FoxP3 and leads to decreased Treg functionality. Our objective was to compare Sirt1 and FoxP3 expressions in Hodgkin lymphoma infiltrating lymphocytes (HLIL) and confirm Sirt1 expression in HRS cells.
  
  
  METHODS
  Immunohistochemical staining of paraffin-embedded tissue with antibodies to Sirt1, FoxP3, TIA-1, and CD8 was performed. Expression of Sirt1 was assessed in both the HRS cells and in the HLILs in twenty-four cases. Adequate tissue was available in 13 cHL cases to permit the enumeration of FoxP3, TIA-1 and CD8 by giving their percent staining of HLILs.
  
  
  RESULTS
  In HLILs, nuclear expression of Sirt1 was 32-88% (mean 67%); FoxP3 expression was 9-40% (mean 23.9%); TIA-1 expression was 15-87% (mean 32%); and CD8 expression was 10-45% (mean = 31%). Sirt1 to FoxP3 ratio was 0.96-5.5 (mean 3.2). TIA-1 to FoxP3 ratio was 0.6-5.1 (mean 1.6). CD8 to FoxP3 ratio was 0.43-3.7 (mean 1.5). There was a difference of Sirt1 to FoxP3 ratios between remission and recurrence groups, being significantly higher in the recurrence group (P = 0.005). Sirt1 demonstrated high nuclear expression in the HRS cells of 21 out of 24 (88%) cases analyzed.
  
  
  CONCLUSIONS
  The relative overexpression of Sirt1 to FoxP3 in HLILs may be considered possible targets for immune modulation. Histone deacetylase inhibitors may increase the efficacy of existing treatment regimens by downregulating SIRT1 gene mRNA/Sirt1 protein function and together with rapamycin could expand the T regulatory/FoxP3 population and functionality and improve prognosis for remission in cHL. Targeting Sirt1 in the HRS cells may facilitate their ability to promote naïve T cell differentiation toward Treg cells over CTL.
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth-Medical School at Houston Houston, USA.
authors.forename: Andrés E
authors.initials: AE
authors.lastname: Quesada
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth-Medical School at Houston Houston, USA.
authors.forename: Binara
authors.initials: B
authors.lastname: Assylbekova
authors.affiliation: Cunningham Pathology Birmingham, Alabama, USA.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Jabcuga
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth-Medical School at Houston Houston, USA.
authors.forename: Rongzhen
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth-Medical School at Houston Houston, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Covinsky
authors.affiliation: Department of Internal Medicine, Division of Oncology, UTHealth-Medical School at Houston Houston, USA.
authors.forename: Adan
authors.initials: A
authors.lastname: Rios
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth-Medical School at Houston Houston, USA.
authors.forename: Nghia D
authors.initials: ND
authors.lastname: Nguyen
authors.affiliation: Department of Pathology and Laboratory Medicine, UTHealth-Medical School at Houston Houston, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Brown
mesh_terms: D016827:CD8 Antigens / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006689:Hodgkin Disease / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism* / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology; D039102:Poly(A)-Binding Proteins / Q000378:metabolism; D011379:Prognosis; D016539:Reed-Sternberg Cells / Q000378:metabolism* / Q000473:pathology; D056564:Sirtuin 1 / Q000378:metabolism*; D000074019:T-Cell Intracellular Antigen-1
chemical_list: D016827:CD8 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D039102:Poly(A)-Binding Proteins; D000074019:T-Cell Intracellular Antigen-1; C071558:TIA1 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: FoxP3; Hodgkin lymphoma; Sirt1; immune dysregulation; morphoproteomics