Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T-cell anergy in vivo

Eur J Immunol. 2009 Aug;39(8):2184-94. doi: 10.1002/eji.200939348.


Tumor-specific CD8 T-cell peripheral tolerance occurs through clonal deletion, suppression, and the induction of anergy and can limit the generation of anti-tumor immunity. Several groups have demonstrated that prostate cancer can render tumor-specific CD8 T cells anergic, suggesting reversing tumor-induced anergy may greatly augment anti-tumor immunity. Recent work has demonstrated that signaling through the OX40 (CD134) co-stimulatory receptor, a member of the TNFR super-family, can augment CD4 and CD8 T-cell expansion, differentiation, and the generation of memory cells. However, whether OX40 ligation can reverse CD8 T-cell anergy, and more specifically, tumor-induced CD8 T-cell anergy, remains unclear. In the current study, we demonstrate that OX40 ligation can reverse CD8 T-cell anergy to a prostate-specific self-Ag in non-tumor-bearing hosts. Furthermore, OX40 engagement reversed tumor-specific CD8 T-cell anergy and restored the proliferative capacity of tumor-reactive CD8 T cells, which attenuated tumor growth and enhanced the survival of tumor-bearing hosts. These data demonstrate that OX40 ligation can rescue the function of anergic self- or tumor-reactive CD8 T cells in vivo and suggests that OX40-mediated therapy may provide a novel means of boosting anti-tumor immunity by restoring the responsiveness of previously anergic tumor-specific CD8 T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Differentiation / immunology
  • Cell Line, Tumor
  • Clonal Anergy / genetics
  • Clonal Anergy / immunology*
  • Cytotoxicity, Immunologic / immunology
  • Flow Cytometry
  • Immunotherapy, Adoptive
  • Interleukin-2 Receptor alpha Subunit / metabolism
  • Interleukin-7 Receptor alpha Subunit / metabolism
  • L-Selectin / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Prostatic Neoplasms / immunology*
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / therapy
  • Receptors, OX40 / genetics
  • Receptors, OX40 / immunology*
  • Signal Transduction / immunology
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism


  • Antigens, Neoplasm
  • Interleukin-2 Receptor alpha Subunit
  • Interleukin-7 Receptor alpha Subunit
  • Receptors, OX40
  • L-Selectin