title: Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy.
abstract: In vitro, engagement of GITR on Treg cells by the agonistic anti-GITR mAb, DTA-1, appears to abrogate their suppressive function. The consequence of in vivo engagement of GITR by DTA-1 is, however, less clear. In this study, we show that Treg cells isolated from DTA-1-treated mice were as potent as those from untreated mice in suppressing conventional CD4 T cells in vitro, indicating that in vivo GITR ligation does not disable Treg cells. Treatment of Foxp3/GFP knock-in mice with DTA-1 led to a selective reduction of circulating Treg cells, suggesting that DTA-1 is a depleting mAb which preferentially targets Treg cells. In tumour-bearing mice, DTA-1-mediated depletion of Treg cells was most marked in tumours but not in tumour-draining lymph node. These features were confirmed in an adoptive transfer model using tumour antigen-specific Treg cells. Interestingly, Treg cells detected in tumour tissues expressed much higher levels of GITR than those in tumour-draining lymph nodes, indicating that the efficiency of depletion might be correlated with the level of GITR expression. Finally, in vivo labelling of GITR in naive or tumour-bearing mice demonstrated that Treg cells constitutively expressed higher levels of GITR than conventional T cells, independent of location and activation state, consistent with the preferential in vivo depletion of Tregs by DTA-1. Thus, depletion of Treg cells represents a previously unrecognised in vivo activity of DTA-1 which has important implications for the application of anti-GITR antibodies in cancer immunotherapy.
authors.affiliation: Department of Immunology, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Coe
authors.forename: Shaima
authors.initials: S
authors.lastname: Begom
authors.forename: Caroline
authors.initials: C
authors.lastname: Addey
authors.forename: Matthew
authors.initials: M
authors.lastname: White
authors.forename: Julian
authors.initials: J
authors.lastname: Dyson
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: Chai
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D055879:Gene Knock-In Techniques; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007167:Immunotherapy; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse