Enhancement of T-cell-mediated anti-tumour immunity via the ectopically expressed glucocorticoid-induced tumour necrosis factor receptor-related receptor ligand (GITRL) on tumours.
Glucocorticoid-induced tumour necrosis factor receptor-related receptor (GITR) costimulates functions of both effector and regulatory T cells. The administration of agonistic anti-GITR monoclonal antibodies efficiently enhances various T-cell-mediated immune responses; however, it is unknown to what extent the ligand of GITR (GITRL) contributes to T-cell responses. We investigated the involvement of endogenously expressed GITRL on dendritic cells and ectopically expressed GITRL on tumours in T-cell-mediated immunity. Expression of GITRL on dendritic cells in secondary lymphoid organs was limited, and treatment with anti-GITRL monoclonal antibodies did not substantially affect T-cell-mediated immunity to alloantigens, a specific protein antigen (ovalbumin), or tumour antigens. The introduction of GITRL promoted anti-tumour immunity in four tumour models. Tumour-associated GITRL greatly augmented the effector function of CD8(+) T cells and enhanced the contribution of CD8(+) T cells. These events reduced the crucial contribution of CD25(+) CD4(+) regulatory T cells, which were found to inhibit immunity against tumours lacking GITRL. Peritumoral injection of GITRL tumour vaccine efficiently inhibited the growth of established tumours. Our results suggest that the ectopic expression of GITRL in tumour cells enhances anti-tumour immunity at peripheral tumour sites. Consequently, the combined use of a GITRL tumour vaccine with methods aimed at enhancing the activation of host antigen-presenting cells in secondary lymphoid tissues may be a promising strategy for tumour immunotherapy.
Piao
Jinhua
J
Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
Kamimura
Yosuke
Y
Iwai
Hideyuki
H
Cao
Yujia
Y
Kikuchi
Keisuke
K
Hashiguchi
Masaaki
M
Masunaga
Taro
T
Jiang
Hongsi
H
Tamura
Kouichi
K
Sakaguchi
Shimon
S
Azuma
Miyuki
M
D000818:Animals; D019496:Cancer Vaccines / Q000627:therapeutic use; D003713:Dendritic Cells / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007111:Immunity, Cellular; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000628:therapy; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014162:Transfection; D048069:Tumor Necrosis Factors / Q000276:immunology*
D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D008024:Ligands; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors