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

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

Research output: Contribution to journalArticle

Abstract

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
Volume176
Issue number2
StatePublished - Jan 15 2006

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Neoplasm Antigens
Granulocyte-Macrophage Colony-Stimulating Factor
Vaccination
T-Lymphocytes
Vaccines
Immune Tolerance
Epitopes
Immunity
Neoplasms
Breast

ASJC Scopus subject areas

  • Immunology

Cite this

OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen. / Murata, Satoshi; Ladle, Brian; Kim, Peter S.; Lutz, Eric R.; Wolpoe, Matthew E.; Ivie, Susan E.; Smith, Holly M.; Armstrong, Todd D; Emens, Leisha A.; Jaffee, Elizabeth; Reilly, R. Todd.

In: Journal of Immunology, Vol. 176, No. 2, 15.01.2006, p. 974-983.

Research output: Contribution to journalArticle

Murata, Satoshi ; Ladle, Brian ; Kim, Peter S. ; Lutz, Eric R. ; Wolpoe, Matthew E. ; Ivie, Susan E. ; Smith, Holly M. ; Armstrong, Todd D ; Emens, Leisha A. ; Jaffee, Elizabeth ; Reilly, R. Todd. / OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen. In: Journal of Immunology. 2006 ; Vol. 176, No. 2. pp. 974-983.
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abstract = "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.",
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AU - Murata, Satoshi

AU - Ladle, Brian

AU - Kim, Peter S.

AU - Lutz, Eric R.

AU - Wolpoe, Matthew E.

AU - Ivie, Susan E.

AU - Smith, Holly M.

AU - Armstrong, Todd D

AU - Emens, Leisha A.

AU - Jaffee, Elizabeth

AU - Reilly, R. Todd

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N2 - 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.

AB - 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.

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