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Cohen AD , Schaer DA , Liu CL , Li YY , Hirschhorn-Cymmerman D , Kim SC , Diab A , Rizzuto G , Duan F , Perales MA , Merghoub T , Houghton AN , Wolchok JD
Agonist Anti-GITR Monoclonal Antibody Induces Melanoma Tumor Immunity in Mice by Altering Regulatory T Cell Stability and Intra-Tumor Accumulation
Plos One. 2010 May;5(5)
PMID: ISI:000277240300012    PMCID: PMCID: PMC2862699    
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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.
Notes
Cohen, Adam D. Schaer, David A. Liu, Cailian Li, Yanyun Hirschhorn-Cymmerman, Daniel Kim, Soo Chong Diab, Adi Rizzuto, Gabrielle Duan, Fei Perales, Miguel A. Merghoub, Taha Houghton, Alan N. Wolchok, Jedd D. ASCO Young Investigator Award ; Charles A. Dana Foundation ; H-C Fellowship ; NIH [K08CA127143-01, K08CA10260, K12 CA120121-01]; MSKCC ; NIH/NCI [T32 CA09149-30, CA56821, CA47179, CA33049, CA59350]; John D. Proctor Foundation ; Damon Runyon-Lilly Clinical Investigator Award [CA56821, CA33049, CA59350]; Damon Runyon-Lilly Foundation ; Swim Across America ; Lita Annenberg Hazen Foundation ; TJ Martell Foundation ; Louis & Anne Abrons Foundation ; Mr. and Mrs. Quentin J. Kennedy Fund ; Mr. William H. Goodwin and Mrs. Alice Goodman Funds ; MSKCC Experimental Therapeutics Center Funding: ADC (ASCO Young Investigator Award, Charles A. Dana Foundation, H-C Fellowship, and NIH K08CA127143-01). MAP (NIH K08CA10260 and MSKCC Byrne Fund). DAS (NIH Clinical Training for Scholar Grant K12 CA120121-01, NIH/NCI Immunology Training Grant T32 CA09149-30 and John D. Proctor Foundation: Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship Award). JDW CA56821, CA33049 and CA59350 (Damon Runyon-Lilly Clinical Investigator Award). ANH (NIH/NCI (CA56821, CA47179, CA33049 and CA59350) and Damon Runyon-Lilly Foundation). Additional support provided by Swim Across America, Lita Annenberg Hazen Foundation, TJ Martell Foundation, Louis & Anne Abrons Foundation, Mr. and Mrs. Quentin J. Kennedy Fund, Mr. William H. Goodwin and Mrs. Alice Goodman Funds, and MSKCC Experimental Therapeutics Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. 49 Public library science; 185 berry st, ste 1300, san francisco, ca 94107 usa 590pw