Cancer Immunology, Immunotherapy

, Volume 59, Issue 9, pp 1367–1377

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

  • David Coe
  • Shaima Begom
  • Caroline Addey
  • Matthew White
  • Julian Dyson
  • Jian-Guo Chai
Original Article

DOI: 10.1007/s00262-010-0866-5

Cite this article as:
Coe, D., Begom, S., Addey, C. et al. Cancer Immunol Immunother (2010) 59: 1367. doi:10.1007/s00262-010-0866-5

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.

Keywords

Anti-GITR Regulatory T cells Depletion HY Tumour Therapy 

Abbreviations

dLN

Tumour-draining lymph node

pLN

Peripheral LN

nTreg

Natural CD4+CD25+Foxp3+ regulatory T cells

Mar

Marilyn mice

PBL

Peripheral blood lymphocytes

MFI

Mean florescence intensity

Foxp3/GFP

Foxp3/GFP knock-in mice

Supplementary material

262_2010_866_MOESM1_ESM.pdf (697 kb)
(PDF 696 kb)

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • David Coe
    • 1
  • Shaima Begom
    • 1
  • Caroline Addey
    • 1
  • Matthew White
    • 1
  • Julian Dyson
    • 1
  • Jian-Guo Chai
    • 1
  1. 1.Department of ImmunologyImperial College London, Hammersmith HospitalLondonUK