Anti-CD40 conditioning enhances the T-CD8 response to a highly tolerogenic epitope and subsequent immunotherapy of simian virus 40 T antigen-induced pancreatic tumors
Abstrakt
Rapid loss of adoptively transferred tumor-specific CD8(+) T cells (T-CD8) following Ag recognition in the periphery and their limited accumulation within the tumor stroma reduces the effectiveness of T cell-based immunotherapy. To better understand the role of T-CD8 in the control of autochthonous tumors, we have used mice of the RIP1-Tag4 lineage that develop pancreatic beta cell tumors due to expression of the SV40 large T Ag from the rat insulin promoter.
We previously showed that the kinetics of functional T-CD8 tolerance varies toward two distinct epitopes derived from T Ag. Epitope I ((206)SAINNYAQKL(215))-specific T-CD8 are rapidly deleted whereas T-CD8 targeting epitope IV (404VVYDFLKC411) persist over the lifetime of tumor-bearing animals.
In this report, we show that the conditioning of tumor-bearing RIP1-Tag4 mice with agonistic anti-CD40 Ab induces extensive expansion of naive epitope I-specific TCR transgenic (TCR-I) T cells in this tolerogenic environment and delays their loss from the