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PW Chen, Z Haskova, AW Taylor, BR Ksander; Ocular Tumors Escape Immune Recognition When Aqueous Humor Imprints Genes That Control Antigen Processing . Invest. Ophthalmol. Vis. Sci. 2002;43(13):883.
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Purpose:Ocular immune privilege allows tumors to escape immune-mediated destruction by regulating both afferent and efferent phases of the immune response. Aqueous humor (AqH), plays an important role in regulating immunity. We hypothesize that ocular tumors escape destruction when AqH induces methylation of genes controlling antigen processing, thus blocking their transcription and preventing expression of crucial tumor antigens. Methods:Transfected P815 tumor cells expressing CD80 and secreting IL-12 were used to immunize DBA/2 mice. Immunized mice received a second tumor challenge into either a subcutaneous site, or the anterior chamber. Tumor growth and mouse survival were recorded. AqH treated tumor cells were cultured with rabbit AqH for 10 days in vitro. Expression of the proteasome subunit LMP-7 was examined by RT-PCR. 5-aza 2-deoxycytydine (5 Aza dC) was used to demethylate AqH treated tumor cells. Results:Immunized mice were protected from a subcutaneous tumor challenge of P815 cells, but not from a tumor challenge into the privileged anterior chamber. To determine the role of AqH in tumor escape, P815 cells were treated with rabbit AqH for 10 days, expanded in culture, and injected into immunized mice. Surprisingly, these tumor cells grew progressively and escaped immune destruction. The tumor escape phenotype was permanent and stable in vitro, even after AqH was removed. AqH treated tumor cells downregulated the proteasome subunit LMP-7. Expression of LMP-7 was restored in tumor cells by treatment with the demethylating agent 5-Aza dC. Tumor escape was not due to either downregulation of MHC class I, or ICAM-1 adhesion molecules. Conclusion:Aqueous humor induces the methylation of LMP-7, a gene that controls antigen processing by degrading cytoplasmic proteins into small peptides. This implies that ocular tumors escape destruction by preventing expression of critical tumor antigens. Since gene methylation is permanent, tumors cells within the eye are imprinted with the immune privileged phenotype and can establish their own privilege when they migrate to a non-privileged site.
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