OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen

Satoshi Murata, Brian H. Ladle, Peter S. Kim, Eric R. Lutz, Matthew E. Wolpoe, Susan E. Ivie, Holly M. Smith, Todd D. Armstrong, Leisha A. Emens, Elizabeth M. Jaffee, R. Todd Reilly

Research output: Contribution to journalArticlepeer-review


T cell costimulation via OX40 is known increase CD4+ T cell expansion and effector function and enhances the development of T cell memory. OX40 costimulation can also prevent, and even reverse, CD4+ T cell anergy. However, the role of OX40 in CD8+ T cell function is less well defined, particularly in the setting of immune tolerance. To determine the effects of OX40 costimulation on the induction of the host CO8+ T cell repertoire to an endogenous tumor Ag, we examined the fate of CD8 + T cells specific for the immunodominant rat HER-2/neu epitope, RNEU420-429, in FVB MMTV-neu (neu-N) mice, which express rat HER-2/neu protein in a predominantly mammary-restricted fashion. We show that the RNEU420-429-specific T cell repertoire in neu-N mice expands transiently after vaccination with a neu-targeted GM-CSF-secreting whole-cell vaccine, but quickly declines to an undetectable level. However, OX40 costimulation, when combined with GM-CSF-secreting tumor-targeted vaccination, can break established CD8+ T cell tolerance in vivo by enhancing the expansion, and prolonging the survival and effector function of CO8+ T cells specific for RNEU420-429. Moreover, we demonstrate thai OX40 expression is up-regulated on both CD4+ and CD8+ T cells shortly after administration of a GM-CSF expressing vaccine. These studies highlight the increased efficacy of OX40 costimulation when combined with a GM-CSF-secreting vaccine, and define a new role for OX40 costimulation of CD8+ T cells in overcoming tolerance and boosting antitumor immunity.

Original languageEnglish (US)
Pages (from-to)974-983
Number of pages10
JournalJournal of Immunology
Issue number2
StatePublished - Jan 15 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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