title: Authentic GITR Signaling Fails To Induce Tumor Regression unless Foxp3+ Regulatory T Cells Are Depleted.
abstract: The glucocorticoid-induced TNFR family-related protein (GITR, TNFRSF18, CD357) is expressed on effector and regulatory T (Treg) cells. Previous studies demonstrated that GITR triggering by anti-GITR mAb enhanced T and B cell-mediated immune responses. GITR-deficient T cells, however, also proliferate more than normal T cells, and this effect is unexplained. Because the activities of mAbs are controlled by their Fc regions, the true effect of GITR signaling needs to be determined by examining its interaction with authentic ligand. Therefore, we generated a pentamerized form of the GITRL extracellular domain (pGITRL) for ligation to GITR and compared its effect on T cells with that of anti-GITR mAb. The pGITRL was more effective than anti-GITR mAb in enhancing the proliferation of effector and regulatory cells in vitro and in vivo. Nonetheless, the growth of MC38 adenocarcinoma cells in vivo was only suppressed for initial 15 d by pGITRL, whereas it was suppressed indefinitely by anti-GITR mAb. Detailed analysis revealed that pGITRL induced extensive proliferation of Foxp3(+)CD4(+) Treg cells and led to the accumulation of activated Treg cells in tumor tissue and draining lymph nodes. Because GITR signaling could not neutralize the suppressive activity of activated Treg cells, pGITRL seems to lose its adjuvant effect when sufficient activated Treg cells have accumulated in the lymph nodes and tumor tissue. Indeed, the antitumor effects of pGITRL were markedly enhanced by depleting CD4(+) cells. These results suggest that GITR signaling has stimulatory effects on effector T cells and inhibitory effects through Treg cells.
authors.affiliation: Biomedicine Production Branch, National Cancer Center, Gyeonggi, 410-769, Republic of Korea;
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi, 410-769, Republic of Korea;
authors.forename: Su M
authors.initials: SM
authors.lastname: Shin
authors.affiliation: Biomedicine Production Branch, National Cancer Center, Gyeonggi, 410-769, Republic of Korea; Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi, 410-769, Republic of Korea;
authors.forename: Beom K
authors.initials: BK
authors.lastname: Choi
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi, 410-769, Republic of Korea;
authors.forename: Ho S
authors.initials: HS
authors.lastname: Oh
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi, 410-769, Republic of Korea;
authors.forename: Chang H
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi, 410-769, Republic of Korea;
authors.forename: Seung J
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi, 410-769, Republic of Korea;
authors.forename: Kwang H
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi, 410-769, Republic of Korea;
authors.forename: Don G
authors.initials: DG
authors.lastname: Lee
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi, 410-769, Republic of Korea;
authors.forename: Sang H
authors.initials: SH
authors.lastname: Park
authors.affiliation: Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Gyeonggi, 410-769, Republic of Korea; Program for Immunotherapeutic Research, National Cancer Center, Gyeonggi, 410-769, Republic of Korea; and Section of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112 bskwon@ncc.re.kr.
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053450:Glucocorticoid-Induced TNFR-Related Protein / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000276:immunology*; D011485:Protein Binding; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors