title: Anti-CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor-infiltrating Tregs in an ovarian cancer xenograft humanized mouse model.
abstract: Recent studies have demonstrated that regulatory T cells (Tregs) are recruited to tumor sites where they can suppress antitumor immunity. The chemokine receptor CCR4 is expressed at high levels on functional CD4+CD25+FoxP3+Tregs and production of the CCR4 ligand CCL22 by tumor cells and tumor-associated macrophages is associated with Treg recruitment to the tumor site. Here, we tested IgG1 and IgG4 isotypes of human anti-CCR4 mAb2-3 for theirin vitroactivity andin vivocapacity in a NSG mouse model bearing CCL22-secreting ovarian cancer (OvCA) xenograft to modulate Tregs and restore antitumor activity. Both mAb2-3 isotypes blockedin vitrochemoattraction of Tregs to CCL22-secreting OvCA cells. However, they differed in theirin vivomode of action with IgG1 causing Treg depletion and IgG4 blocking migration to the tumors. Primary T cells that were primed with OvCA-pulsed dendritic cells (DCs) demonstrated INFγ secretion that could be enhanced through Treg depletion by mAb2-3. Humanized mice reconstructed with allogeneic tumor-primed T cells (TP-T) were used to evaluate the restoration of OvCA immunity by depletion or blockade of Tregs with mAb2-3. We observed that IgG1 was more potent than IgG4 in inhibiting tumor growth. Mechanism studies demonstrated that mAb2-3 treatment lead to inhibition of IL-2 binding to its receptor. Further studies showed that mAb2-3 induced CD25 shedding (sCD25) from Tregs which lead to a decrease in IL-2-dependent survival. Together, the results demonstrate that mAb2-3 is an agonist antibody that can restore anti-OvCA immunity through modulation of Treg activity.
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: De-Kuan
authors.initials: DK
authors.lastname: Chang
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, MA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Peterson
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, MA, USA.
authors.forename: Jiusong
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, MA, USA.
authors.forename: Calum
authors.initials: C
authors.lastname: Goudie
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; Ovarian Cancer Research Center, Department of Obstetrics & Gynecology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
authors.forename: Ronny I
authors.initials: RI
authors.lastname: Drapkin
authors.affiliation: Department of Medicine, Harvard Medical School, Boston, MA, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Joyce F
authors.initials: JF
authors.lastname: Liu
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute , Boston, MA, USA.
authors.forename: Ursula
authors.initials: U
authors.lastname: Matulonis
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhu
authors.affiliation: Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Marasco
keywords: CCR4; immunotherapy; monoclonal antibody; ovarian cancer; regulatory T cells