Journal Article

Depletion of regulatory T cells by anti-GITR mAb as a novel mechanism for cancer immunotherapy

White, Matthew, Dyson, Julian, Coe, David, Addey, Caroline, Begom, Shaima, Chai, Jian-Guo

2010

Overview

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.

• Publisher: Berlin/Heidelberg : Springer-Verlag,Springer-Verlag,Springer,Springer Nature B.V
• Subject: Adoptive Transfer / Animals / Anti-GITR / Antibodies, Monoclonal / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - therapeutic use / Antigens / Antigens, Neoplasm / Antigens, Neoplasm - immunology / Antineoplastic agents / Biological and medical sciences / Cancer Research / Cell Line, Tumor / Depletion / Forkhead Transcription Factors / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - immunology / Forkhead Transcription Factors - metabolism / Gene Knock-In Techniques / genetics / Glucocorticoid-Induced TNFR-Related Protein / Immunology / Immunotherapy / Lymphocyte Depletion / Lymphocytes / Male / Medical research / Medical sciences / Medicine / Medicine & Public Health / metabolism / Mice / Mice, Inbred C57BL / Mice, Inbred CBA / Mice, Transgenic / Neoplasm Transplantation / Oncology / Original / Original Article / pathology / Pharmacology. Drug treatments / Rats / Receptors, Nerve Growth Factor / Receptors, Nerve Growth Factor - genetics / Receptors, Nerve Growth Factor - immunology / Receptors, Nerve Growth Factor - metabolism / Receptors, Tumor Necrosis Factor / Receptors, Tumor Necrosis Factor - genetics / Receptors, Tumor Necrosis Factor - immunology / Receptors, Tumor Necrosis Factor - metabolism / Regulatory T cells / Scholarships & fellowships / T-Lymphocytes, Regulatory / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - metabolism / T-Lymphocytes, Regulatory - pathology / therapeutic use / therapeutics / therapy / Tumor necrosis factor-TNF / Tumour / Urinary Bladder Neoplasms / Urinary Bladder Neoplasms - immunology / Urinary Bladder Neoplasms - pathology / Urinary Bladder Neoplasms - therapy