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 agonist.
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.
Redmond
William L
WL
Earle A Chiles Research Institute, Robert W Franz Cancer Research Center, Providence Portland Medical Center, Portland, OR 97213, USA.
Gough
Michael J
MJ
Charbonneau
Bridget
B
Ratliff
Timothy L
TL
Weinberg
Andrew D
AD
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D053804:Granzymes / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000276:immunology*; D053262:Receptors, OX40 / Q000819:agonists*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000906:Antibodies; D000951:Antigens, Neoplasm; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D053804:Granzymes