Ligation of the OX40 co-stimulatory receptor reverses self-Ag and tumor-induced CD8 T-cell anergy in vivo.
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.
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
Weinberg
Andrew D
AD
D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D017635:Clonal Anergy / Q000235:genetics / Q000276:immunology*; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D016219:Immunotherapy, Adoptive; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D019041:L-Selectin / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D053262:Receptors, OX40 / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000951:Antigens, Neoplasm; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; D053262:Receptors, OX40; D019041:L-Selectin