Anti-CD40 conditioning enhances the TCD8 response to a highly tolerogenic epitope and subsequent immunotherapy of simian virus 40 T antigen-induced pancreatic tumors

Pavel Otahal, Barbara B. Knowles, Satvir S. Tevethia, Todd D. Schell

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Rapid loss of adoptively transferred tumor-specific CD8+ T cells (TCD8) 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 TCD8 in the control of autochthonous tumors, we have used mice of the RIP1-Tag4 lineage that develop pancreatic β cell tumors due to expression of the SV40 large T Ag from the rat insulin promoter. We previously showed that the kinetics of functional TCD8 tolerance varies toward two distinct epitopes derived from T Ag. Epitope I (206SAINNYAQKL215)-specific TCD8 are rapidly deleted whereas TCD8 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 host. In addition, functional TCR-I T cells intensively infiltrate pancreatic tumors, resulting in increased survival of RIP1-Tag4 mice. These results suggest that a similar approach could effectively enhance T cell-based immunotherapies to cancer when targeting other highly tolerogenic epitopes.

Original languageEnglish (US)
Pages (from-to)6686-6695
Number of pages10
JournalJournal of Immunology
Volume179
Issue number10
DOIs
StatePublished - Nov 15 2007

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

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