title: Role of Epigenetic Modification and Immunomodulation in a Murine Prostate Cancer Model.
abstract: Decreased expression of highly immunogenic cancer-testis antigens (CTA) might help tumor to achieve low immunogenicity, escape immune surveillance and grow unimpeded. Our aim was to evaluate CTA expression in tumor and normal tissues and to investigate possible means of improving the immune response in a murine prostate cancer (CaP) model by using the combination of epigenetic modifier 5-azacitidine (5-AzaC) and immunomodulator lenalidomide. No study to date has examined the effect of this combination on the prostate cancer or its impact on antigen-presenting cells (APC).
  
  
  
  Gene microarrays were performed to compare expression of several CTA in murine prostate cancer (RM-1 cells) and normal prostate. RM-1 cells were treated with 5-AzaC and real-time PCR was performed to investigate the expression of several CTA. Western blotting was used to determine whether expression of CTA-specific mRNA induced by 5-AzaC resulted in increase in the corresponding protein. Effect of the epigenetic agents and immunomodulators was assessed on dendritic cells (DC) using flow cytometry, ELISA and T-cell proliferation assay.
  
  
  
  Gene arrays demonstrated decreased expression of 35 CTA in CaP tissue compared to normal prostate. 5-AzaC treatment of RM-1 prostate cancer cells upregulated the expression of all 13 CTA tested in a dose-dependent fashion. DC were treated with 5-AzaC and lenalidomide and the expression of surface markers MHC Class I, MHC Class II, CD80, CD86, CD 205, and CD40 was increased. Combination of 5-AzaC and lenalidomide enhances the ability of DC to stimulate T-cell proliferation in mixed leukocyte reaction. Secretion of IL-12 and IL-15 by DC increased significantly with addition of 5-AzaC or 5-AzaC and lenalidomide.
  
  
  
  Decreased expression of CTA by prostate cancer may be a means of escaping immune monitoring. Combination of epigenetic modifications and immunomodulation by 5-AzaC and lenalidomide increased tumor immunogenicity and enhanced DC function and may be used in the treatment of advanced prostate cancer. Prostate 77: 361-373, 2017. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia.
authors.forename: Jay E
authors.initials: JE
authors.lastname: Sulek
authors.affiliation: Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia.
authors.forename: Samuel P
authors.initials: SP
authors.lastname: Robinson
authors.affiliation: Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia.
authors.forename: Albert A
authors.initials: AA
authors.lastname: Petrossian
authors.affiliation: Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia.
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia.|Massey Cancer Center, Virginia Commonwealth University Medical Center, Richmond, Virginia.
authors.forename: Ekaterine
authors.initials: E
authors.lastname: Goliadze
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University Medical Center, Richmond, Virginia.|Department of Microbiology and Immunology, Virginia Commonwealth University School of Medicine, Richmond, Virginia.
authors.forename: Masoud H
authors.initials: MH
authors.lastname: Manjili
authors.affiliation: Massey Cancer Center, Virginia Commonwealth University Medical Center, Richmond, Virginia.
authors.forename: Amir
authors.initials: A
authors.lastname: Toor
authors.affiliation: Division of Urology, Department of Surgery, Virginia Commonwealth University Medical Center, Richmond, Virginia.|Massey Cancer Center, Virginia Commonwealth University Medical Center, Richmond, Virginia.
authors.forename: Georgi
authors.initials: G
authors.lastname: Guruli
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D007155:Immunologic Factors / Q000494:pharmacology; D056747:Immunomodulation / Q000187:drug effects / Q000502:physiology*; D000077269:Lenalidomide; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D007155:Immunologic Factors; D013792:Thalidomide; D000077269:Lenalidomide
keywords: 5-azacitidine; dendritic cells; epigenetic modulation; lenalidomide; prostate cancer