title: Stimulation of the glucocorticoid-induced TNF receptor family-related receptor on CD8 T cells induces protective and high-avidity T cell responses to tumor-specific antigens.
abstract: Treatment of tumor-bearing mice with a stimulatory Ab to glucocorticoid-induced TNFR family-related receptor (GITR) has previously been shown to elicit protective T cell responses against poorly immunogenic tumors. However, the role of GITR stimulation on CD8 T cells and the nature of tumor rejection Ags have yet to be determined. In this study, we show that a stimulatory mAb to GITR (clone DTA-1) acts directly on CD8 T cells, but not on CD4(+)CD25(+) regulatory T (T(reg)) cells, in B16 tumor-bearing mice to induce concomitant immunity against secondary B16 tumors, as well as protective memory following surgical excision of the primary tumor. Melanoma growth itself induced GITR expression on tumor-specific CD8 T cells, providing a mechanism whereby these cells may respond to stimulatory anti-GITR. Unexpectedly, in contrast to T(reg) cell depletion therapy with anti-CD4, GITR stimulation induced very weak CD8 T cell responses to melanocyte differentiation Ags expressed by the tumor, and did not induce autoimmune vitiligo. Accordingly, GITR-stimulated hosts that were primed with B16 melanoma rejected B16, but not the unrelated JBRH melanoma, indicating that tumor rejection Ags are tumor-specific rather than shared. In support of this, we show that GITR stimulation induces CD8 T cell responses to a tumor-specific Ag, and that these responses are of higher functional avidity compared with those induced by T(reg) cell depletion. We conclude that stimulation of GITR on effector CD8 T cells results in high-avidity T cell responses to tumor-specific Ags, thereby inducing potent antitumor immunity in the absence of autoimmunity.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth Medical School, Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
authors.forename: Anik L
authors.initials: AL
authors.lastname: Côté
authors.forename: Peisheng
authors.initials: P
authors.lastname: Zhang
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: O'Sullivan
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Jacobs
authors.forename: Carli R
authors.initials: CR
authors.lastname: Clemis
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
authors.forename: José A
authors.initials: JA
authors.lastname: Guevara-Patiño
authors.forename: Mary Jo
authors.initials: MJ
authors.lastname: Turk
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion / Q000276:immunology; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017475:Receptors, Nerve Growth Factor / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D000951:Antigens, Neoplasm; D018984:Epitopes, T-Lymphocyte; D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse