May 2004
Volume 45, Issue 13
ARVO Annual Meeting Abstract  |   May 2004
The Ocular Environment Induces Epigenetic Changes in Tumor Cells That Leads to Immune Escape
Author Affiliations & Notes
  • P.W. Chen
    Ophthalmology, Schepens Eye Research Institute, Boston, MA
  • L.L. Y. Chun
    Ophthalmology, Schepens Eye Research Institute, Boston, MA
  • B.R. Ksander
    Ophthalmology, Schepens Eye Research Institute, Boston, MA
  • Footnotes
    Commercial Relationships  P.W. Chen, None; L.L.Y. Chun, None; B.R. Ksander, None.
  • Footnotes
    Support  RO1 EY08222
Investigative Ophthalmology & Visual Science May 2004, Vol.45, 4521. doi:
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      P.W. Chen, L.L. Y. Chun, B.R. Ksander; The Ocular Environment Induces Epigenetic Changes in Tumor Cells That Leads to Immune Escape . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4521.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract: : Purpose:We previously demonstrated that tumors growing within the eye rapidly develop a tumor escape phenotype in which tumor cells acquire their own capacity to avoid immune elimination. Surprisingly, the escape phenotype was permanent, and passed onto progeny cells during DNA replication. Since this can only occur from either genomic or epigenetic changes in DNA, we hypothesized that the ocular environment induces epigenetic changes in tumor cells that leads to the immune escape phenotype. DNA methylation is an important epigenetic mechanism, in which methylation of cytosine at CpG dinucleotides is enzymatically mediated by de novo methyltransferases, such as Dnmt3b. Methylation of gene promoters permanently blocks gene transcription. Methods:Eye–derived tumor cells were established by injecting P815 tumor cells into the anterior chamber of naïve syngeneic DBA/2 mice: tumor cells were recovered 10 days later. Immunized DBA/2 mice were generated by subcutaneous injections of P815 cells transfected with CD80+IL–12. RNA from P815 and eye–derived P815 cells was reverse transcribed to cDNA and hybridized to murine genome specific microarray slides. Data was analyzed using a BioArray Software Environment database server. Protein lysates of tumor cells were analyzed by Western blot using de novo methyltransferase specific antibodies and quantitated by densitometry. 5–aza 2–deoxycytydine (5 Aza dC) was used to demethylate tumor cells. Results:Eye–derived tumor cells displayed the escape phenotype and grew progressively in the flank of immunized mice. Induction of the immune escape phenotype coincided with an increased expression of the de novo methyltransferase Dnmt3b. Microarray analysis revealed a 3.3 fold increase in Dnmt3b in eye–derived P815 cells (significant in 4 independent assays, p< 0.00011). Western blot analysis confirmed Dnmt3b was expressed at higher levels in eye–derived tumor cells. Treating eye–derived tumors with the DNA de–methylating reagent 5 Aza dC reversed the escape phenotype triggering immune elimination. Conclusion:Ocular tumors acquire an immune escape phenotype caused by silencing genes via activation of methyltransferases that mediate de novo DNA methylation.

Keywords: immune tolerance/privilege • immunomodulation/immunoregulation • anterior segment 

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