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H.W. Mensink, P.W. Chen, C.L. Lindenhovius, M.J. Jager, B.R. Ksander; Ocular Tumor Escape in Transgenic T Cell Mice With a High Percentage of Tumor Antigen-Specific CD8+ T Cells . Invest. Ophthalmol. Vis. Sci. 2003;44(13):760.
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Purpose: We previously found that P815 tumor cells growing within the immune privileged anterior chamber undergo an epigenetic change that allows "eye-derived" tumor cells to escape rejection when re-injected into the non-privileged flank of immunized mice. Our data suggest tumors escape via a defect in the Class I antigen-processing pathway. Unfortunately, P815 tumor cells express multiple tumor antigens, making it difficult to identify precisely the epigenetic change that controls antigen processing and leads to tumor escape. For this reason, we undertook this study using the murine CMS-5 fibrosarcoma that expresses a single tumor antigen (tERK) that is presented by H-2Kd Class I. ERK is a kinase that is required for tumor cell proliferation; thereby preventing development of any escape mechanism involving down-regulation of ERK expression. Therefore, CMS-5 tumor cells require an escape mechanism that allows ERK to be expressed within the cell, but prevents the tumor antigen from being processed and presented on the cell surface. Methods and Results: CMS-5 tumors were originally derived from BALB/c mice and grow progressively when injected into the flank. By contrast, CMS-5 tumors are rejected completely by day 12 when injected into the flank of DUC-18 TcR transgenic BALB/c mice that have 80% of their T cells specific for the tERK tumor antigen. CMS-5 tumors experience immune privilege when injected into the anterior chamber of DUC-18 mice and survive for an extended time (30 days). To determine if CMS-5 tumor cells undergo an epigenetic change within the eye that allows tumor escape, "eye-derived" CMS-5 tumor cells were recovered from the anterior chamber at 10 days, cultured for 5 passages in vitro, and re-injected into the flank of another group of DUC-18 mice. Even though of 80% of DUC-18 CD8+ T cells are specific for the tERK tumor antigen, the eye-derived tumors grew progressively and were not rejected. Conclusions: Tumor cells within the eye undergo a change that allows them to escape specific T cells even when a majority of the CD8+ T cells in the mouse are tumor antigen-specific. Since the CMS-5 tumors express a single genetically characterized antigen, this model should allow us to identify precisely the changes in antigen processing that lead to tumor escape. EY-08222
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