OX40 Costimulation Synergizes with GM-CSF Whole-Cell Vaccination to Overcome Established CD8+ T Cell Tolerance to an Endogenous Tumor Antigen

• Published in: The Journal of immunology (1950) 2006-01, Vol.176 (2), p.974-983
• Main Authors: Murata, Satoshi, Ladle, Brian H, Kim, Peter S, Lutz, Eric R, Wolpoe, Matthew E, Ivie, Susan E, Smith, Holly M, Armstrong, Todd D, Emens, Leisha A, Jaffee, Elizabeth M, Reilly, R. Todd
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Neoplasm; Cancer Vaccines - administration & dosage; Cancer Vaccines - genetics; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Female; Glycoproteins - immunology; Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Immune Tolerance; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - therapy; Mice; Mice, Transgenic; NIH 3T3 Cells; Peptide Fragments - immunology; Rats; Receptor, ErbB-2; Receptors, OX40; Receptors, Tumor Necrosis Factor - administration & dosage; Recombinant Proteins; T-Lymphocytes, Helper-Inducer - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.176.2.974

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.