CD8+ T Cells Targeting A Single Immunodominant Epitope Are Sufficient for Elimination of Established SV40 T Antigen-Induced Brain Tumors

摘要

Immunotherapy of established solid tumors is rarely achieved and the mechanisms leading to success remain to be elucidated. We previously showed that extended control of advanced-stage autochthonous brain tumors is achieved following adoptive transfer of naïve C57BL/6 splenocytes into sublethally irradiated line SV11 mice expressing the SV40 T antigen (T Ag) oncoprotein, and was associated with in vivo priming of CD8⁺ T cells (TCD8) specific for the dominant epitope IV (T Ag residues 404–411). Using donor lymphocytes derived from mice that are tolerant to epitope IV or a newly characterized transgenic mouse line expressing an epitope IV-specific T cell receptor, we show that epitope IV-specific TCD8 are a necessary component of the donor pool and that purified naïve epitope IV-specific TCD8 are sufficient to promote complete and rapid regression of established tumors. While transfer of naïve TCR-IV cells alone induced some initial tumor regression, increased survival of tumor-bearing mice required prior conditioning of the host with a sublethal dose of gamma irradiation and was associated with complete tumor eradication. Regression of established tumors was associated with rapid accumulation of TCR-IV T cells within the brain following initial priming against the endogenous T Ag in the peripheral lymphoid organs. In addition, persistence of functional TCR-IV cells in both the brain and peripheral lymphoid organs was associated with long-term tumor-free survival. Finally, we show that production of IFNγ, but not perforin or TNFα, by the donor lymphocytes is critical for control of autochthonous brain tumors.