OX40-enhanced tumor rejection and effector T cell differentiation decreases with age.
OX40 agonists have potent immunotherapeutic effects against a variety of murine tumors, yet it is unclear the role that age-related immune senescence plays on their efficacy. We found that middle-aged and elderly tumor-bearing mice (12 and 20 mo old, respectively) treated with anti-OX40 were less responsive compared with young mice 6 mo or less of age. Decreased tumor-free survival was observed in both male and female mice, and was not due to changes in the surface expression of OX40 on T cells in older animals. Enumeration of cytokine-producing effector T cells in tumor-bearing mice revealed a significant decline in these cells in the older mice treated with anti-OX40 compared with their younger counterparts. The decrease of this critical T cell population in middle-aged mice was not a result of inherent T cell deficiencies, but was revealed to be T cell extrinsic. Finally, combining IL-12, an innate cytokine, with anti-OX40 boosted levels of differentiated effector T cells in the older anti-OX40-treated mice and partially restored the defective antitumor responses in the middle-aged mice. Our data show that the anti-OX40-enhancement of tumor immunity and effector T cell numbers is decreased in middle-aged mice and was partially reversed by coadministration of the proinflammatory cytokine IL-12.
Ruby
Carl E
CE
Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR 97213, USA.
Weinberg
Andrew D
AD
D000375:Aging / Q000276:immunology*; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D002454:Cell Differentiation / Q000276:immunology*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D018836:Inflammation Mediators / Q000008:administration & dosage; D018664:Interleukin-12 / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053262:Receptors, OX40 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D012513:Sarcoma, Experimental / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control
D000906:Antibodies; D018836:Inflammation Mediators; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D018664:Interleukin-12