title: Regulating mammalian target of rapamycin to tune vaccination-induced CD8(+) T cell responses for tumor immunity.
abstract: Vaccine strategies aimed at generating CD8(+) T cell memory responses are likely to show augmented efficacy against chronic challenges like tumor. The abundance in variety of memory CD8(+) T cells behooves development of vaccine strategies that generate distinct memory responses and evaluate them for tumor efficacy. In this study, we demonstrate the ability of a variety of rapamycin treatment regimens to regulate virus vaccination-induced CD8(+) T cell memory responses and tumor efficacy. Strikingly, a short course of high-dose, but not low-dose, rapamycin treatment transiently blocks viral vaccination-induced mammalian target of rapamycin activity in CD8(+) T cells favoring persistence and Ag-recall responses over type 1 effector maturation; however, prolonged high-dose rapamycin administration abrogated memory responses. Furthermore, a short course of high-dose rapamycin treatment generated CD8(+) T cell memory responses that were independent of IL-15 and IL-7 and were programmed early for sustenance and greater tumor efficacy. These results demonstrate the impact a regimen of rapamycin treatment has on vaccine-induced CD8(+) T cell responses and indicates that judicious application of rapamycin can augment vaccine efficacy for chronic challenges.
authors.affiliation: Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Qingsheng
authors.initials: Q
authors.lastname: Li
authors.forename: Rajesh
authors.initials: R
authors.lastname: Rao
authors.forename: Joseph
authors.initials: J
authors.lastname: Vazzana
authors.forename: Peter
authors.initials: P
authors.lastname: Goedegebuure
authors.forename: Kunle
authors.initials: K
authors.lastname: Odunsi
authors.forename: William
authors.initials: W
authors.lastname: Gillanders
authors.forename: Protul A
authors.initials: PA
authors.lastname: Shrikant
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology / Q000627:therapeutic use*; D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation; D028121:Canarypox virus / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use*; D060966:Clonal Selection, Antigen-Mediated; D007156:Immunologic Memory / Q000187:drug effects*; D019409:Interleukin-15 / Q000172:deficiency / Q000276:immunology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D046912:Multiprotein Complexes; D009368:Neoplasm Transplantation; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011506:Proteins / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D037182:T-Cell Antigen Receptor Specificity; D058570:TOR Serine-Threonine Kinases; D013945:Thymoma / Q000276:immunology* / Q000628:therapy; D013953:Thymus Neoplasms / Q000276:immunology* / Q000628:therapy; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D019409:Interleukin-15; D046912:Multiprotein Complexes; D011506:Proteins; D010047:Ovalbumin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus