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Defects in the Acquisition of CD8 T Cell Effector Function after Priming with Tumor or Soluble Antigen Can Be Overcome by the Addition of an OX40 Agonist¹

William L. Redmond^*, Michael J. Gough^*, Bridget Charbonneau^,, Timothy L. Ratliff^2, and Andrew D. Weinberg^3,*

^* Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213; and Department of Microbiology and Department of Urology, University of Iowa, Iowa City, IA 52242

Several members of the TNFR superfamily, including OX40 (CD134), 4-1BB (CD137), and CD27 provide critical costimulatory signals that promote T cell survival and differentiation in vivo. Although several studies have demonstrated that OX40 engagement can enhance CD4 T cell responses, the mechanisms by which OX40-mediated signals augment CD8 T cell responses are still unclear. Previously, we and others have shown that OX40 engagement on Ag-specific CD8 T cells led to increased CD8 T cell expansion, survival, and the generation of greater numbers of long-lived memory cells. Currently, we demonstrate that provision of an OX40 agonist during the activation of naive CD8 T cells primed in vivo with either soluble or tumor-associated Ag significantly augments granzyme B expression and CD8 T cell cytolytic function through an IL-2-dependent mechanism. Furthermore, augmented CTL function required direct engagement of OX40 on the responding CD8 T cells and was associated with increased antitumor activity against established prostate tumors and enhanced the survival of tumor-bearing hosts. Thus, in the absence of danger signals, as is often the case in a tumor-bearing host, provision of an OX40 agonist can overcome defective CD8 T cell priming and lead to a functional antitumor response in vivo.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the National Institutes of Health (CA122701-01 and CA102577-05 to A.D.W.), an American Cancer Society–Sam E. and Kathleen Henry Postdoctoral Fellowship (to W.L.R.), and funding from the MJ Murdoch Charitable Trust.

² Current address: Department of Comparative Pathobiology, School of Veterinary Medicine, Purdue Cancer Center, Hansen Life Sciences Research Building, Room 145, 201 South University Street, West Lafayette, IN 47907-2064.

³ Address correspondence and reprint requests to Dr. Andrew D. Weinberg, Earle A. Chiles Research Institute, Robert W. Franz Cancer Research Center, Providence Portland Medical Center, 4805 NE Glisan Street 5F40, Portland, OR 97213. E-mail address: andrew.weinberg{at}providence.org

⁴ Abbreviations used in this paper: OX40L, OX40 ligand; Tg, transgenic; TIL, tumor-infiltrating lymphocyte; mOVA, membrane-bound OVA; LN, lymph node.

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