title: OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumor antigen.
abstract: T cell costimulation via OX40 is known to 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 CD8+ 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 CD8+ T cells specific for RNEU420-429. Moreover, we demonstrate that 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.
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Murata
authors.forename: Brian H
authors.initials: BH
authors.lastname: Ladle
authors.forename: Peter S
authors.initials: PS
authors.lastname: Kim
authors.forename: Eric R
authors.initials: ER
authors.lastname: Lutz
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Wolpoe
authors.forename: Susan E
authors.initials: SE
authors.lastname: Ivie
authors.forename: Holly M
authors.initials: HM
authors.lastname: Smith
authors.forename: Todd D
authors.initials: TD
authors.lastname: Armstrong
authors.forename: Leisha A
authors.initials: LA
authors.lastname: Emens
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
authors.forename: R Todd
authors.initials: RT
authors.lastname: Reilly
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D007108:Immune Tolerance; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D010446:Peptide Fragments / Q000276:immunology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor / Q000008:administration & dosage*; D011994:Recombinant Proteins; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D006023:Glycoproteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D053262:Receptors, OX40; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C505717:Tnfrsf4 protein, mouse; C505718:Tnfrsf4 protein, rat; C483804:Erbb2 protein, rat