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P. W. Chen, D. S. Dace, H. Alizadeh, J. Y. Niederkorn; Tumor Infiltrating CD8+ T Cells Mediate Non-Phthisical Intraocular Tumor Rejection by a TNF- Dependent Mechanism. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2397. doi: https://doi.org/.
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CD4+ T cells mediate a pristine, non-phthisical rejection of adenovirus type 5 early region 1-transformed embryonic tumors (Ad5E1) in an IFN-γ dependent antitumor response. Interestingly, CD8+ T cells also infiltrate intraocular Ad5E1 tumors. In this study, we analyzed CD8+ T cells in the Ad5E1 tumor model to determine their role in mediating non-phthisical intraocular tumor rejection.
Mice were injected in the anterior chamber with the Ad5E1 tumor cells and tumor growth was recorded for 4 weeks. Pure CD8+ T cell populations were obtained by MACS magnetic bead separation followed by anti-CD4 antibody treatment and rabbit complement. Tumor infiltrating T cells were identified by FACS using T cell-specific antibodies. CTL activity was assessed using splenocytes co-cultured with Mitomycin C treated tumor cells in standard 4h 51Cr CTL assays. Ad5E1 MHC class I expression was analyzed by FACS analysis using MHC class I specific antibodies. Cytokine quantitation was assessed by ELISA. Apoptosis was evaluated using Annexin V staining.
Adoptive transfer of purified CD8+ T cells from B6 mice that previously rejected an intraocular tumor into SCID mice conferred protective immunity against an intraocular Ad5E1 tumor challenge. Interestingly, CD8+ mediated tumor cytotoxicity was not due to conventional CTL lysis even though Ad5E1 cells expressed MHC class I molecules. CD8+ T cells did not utilize perforin, IFN-γ, FasL, or TRAIL to mediate tumor rejection. Intraocular Ad5E1 tumors were rejected in TNF-α KO mice. However, SCID mice that received an adoptive transfer of purified CD8+ T cells from TNF-α KO rejector mice failed to reject intraocular Ad5E1 tumors.
CD8+ T cells from B6 mice that reject intraocular Ad5E1 tumors have the capacity to elicit antitumor immunity. However, the CD8+ T cells do not eliminate tumor by conventional CTL mediated lysis, but employ a TNF-α mediated pathway to promote tumor rejection. Together, the data suggests that pristine, non-phthisical Ad5E1 tumor rejection involves a primary IFN-γ dependent CD4+ T cell pathway and a secondary TNF-α dependent CD8+ T cell pathway to mediate rejection of Ad5E1 ocular tumors without sustaining damage to the surrounding ocular tissues.
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