Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation Journal Article

Authors: Cohen, A. D.; Schaer, D. A.; Liu, C.; Li, Y.; Hirschhorn-Cymmerman, D. ; Kim, S. C.; Diab, A.; Rizzuto, G.; Duan, F.; Perales, M. A.; Merghoub, T.; Houghton, A. N.; Wolchok, J. D.
Article Title: Agonist anti-GITR monoclonal antibody induces melanoma tumor immunity in mice by altering regulatory T cell stability and intra-tumor accumulation
Abstract: In vivo GITR ligation has previously been shown to augment T-cell-mediated anti-tumor immunity, yet the underlying mechanisms of this activity, particularly its in vivo effects on CD4+ foxp3+ regulatory T cells (Tregs), have not been fully elucidated. In order to translate this immunotherapeutic approach to the clinic it is important gain better understanding of its mechanism(s) of action. Utilizing the agonist anti-GITR monoclonal antibody DTA-1, we found that in vivo GITR ligation modulates regulatory T cells (Tregs) directly during induction of melanoma tumor immunity. As a monotherapy, DTA-1 induced regression of small established B16 melanoma tumors. Although DTA-1 did not alter systemic Treg frequencies nor abrogate the intrinsic suppressive activity of Tregs within the tumor-draining lymph node, intra-tumor Treg accumulation was significantly impaired. This resulted in a greater Teff:Treg ratio and enhanced tumor-specific CD8+ T-cell activity. The decreased intra-tumor Treg accumulation was due both to impaired infiltration, coupled with DTA-1-induced loss of foxp3 expression in intra-tumor Tregs. Histological analysis of B16 tumors grown in Foxp3-GFP mice showed that the majority of GFP+ cells had lost Foxp3 expression. These "unstable" Tregs were absent in IgG-treated tumors and in DTA-1 treated TDLN, demonstrating a tumor-specific effect. Impairment of Treg infiltration was lost if Tregs were GITR-/-, and the protective effects of DTA-1 were reduced in reconstituted RAG1-/- mice if either the Treg or Teff subset were GITR-negative and absent if both were negative. Our results demonstrate that DTA-1 modulates both Teffs and Tregs during effective tumor treatment. The data suggest that DTA-1 prevents intra-tumor Treg accumulation by altering their stability, and as a result of the loss of foxp3 expression, may modify their intra-tumor suppressive capacity. These findings provide further support for the continued development of agonist anti-GITR mAbs as an immunotherapeutic strategy for cancer. © 2010 Cohen et al.
Keywords: controlled study; protein expression; unclassified drug; histopathology; drug efficacy; drug potentiation; monotherapy; nonhuman; transcription factor foxp3; cd8+ t lymphocyte; cell proliferation; tumor associated leukocyte; cd8-positive t-lymphocytes; forkhead transcription factors; lymphocytes, tumor-infiltrating; animal cell; mouse; animal; metabolism; animals; mice; animal tissue; mus; cancer immunotherapy; melanoma; protein depletion; green fluorescent protein; animal experiment; animal model; in vivo study; pathology; cell line, tumor; mice, inbred c57bl; immunoregulation; c57bl mouse; monoclonal antibody; regulatory t lymphocyte; immunology; antibodies, monoclonal; immunoglobulin g; cancer vaccine; t-lymphocytes, regulatory; lymph node; tumor cell line; melanoma b16; adoptive transfer; tumor immunity; effector cell; tumor necrosis factor receptor; upregulation; immunity; up-regulation; rag1 protein; glucocorticoid induced tumor necrosis factor receptor; forkhead transcription factor; t lymphocyte subpopulation; t lymphocyte activation; foxp3 protein, mouse; receptors, tumor necrosis factor; glucocorticoid induced tumor necrosis factor receptor monoclonal antibody; nerve growth factor receptor; tnfrsf18 protein, mouse; molecular stability; eragrostis tef; receptors, nerve growth factor
Journal Title: PLoS ONE
Volume: 5
Issue: 5
ISSN: 1932-6203
Publisher: Public Library of Science  
Date Published: 2010-05-01
Start Page: :e10436
Language: English
DOI: 10.1371/journal.pone.0010436
PUBMED: 20454651
PROVIDER: scopus
PMCID: PMC2862699
Notes: --- - "Cited By (since 1996): 4" - "Export Date: 20 April 2011" - "Article No. e10436" - "Source: Scopus"
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MSK Authors
  1. Jedd D Wolchok
    672 Wolchok
  2. Taha Merghoub
    211 Merghoub
  3. Adam D Cohen
    42 Cohen
  4. Fei Duan
    6 Duan
  5. Adi Diab
    25 Diab
  6. Miguel-Angel Perales
    384 Perales
  7. Cailian Liu
    37 Liu
  8. David A Schaer
    22 Schaer
  9. Alan N Houghton
    274 Houghton
  10. Yanyun Li
    23 Li
  11. Gabrielle A Rizzuto
    21 Rizzuto
  12. Soo Chong Kim
    1 Kim