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Open Access

FcgRIIIA (CD16)-expressing monocytes mediate the depletion of tumor-infiltrating Tregs via Ipilimumab-dependent ADCC in melanoma patients

  • Emanuela Romano1,
  • Monika Kusio-Kobialka2,
  • Periklis G Foukas3,
  • Helene Bichat2,
  • Petra Baumgaertner4,
  • Christiane Meyer3,
  • Pierluigi Ballabeni5,
  • Olivier Michielin1,
  • Benjamin Weide6,
  • Pedro Romero7 and
  • Daniel E Speiser7
Journal for ImmunoTherapy of Cancer20142(Suppl 3):O14

https://doi.org/10.1186/2051-1426-2-S3-O14

Published: 6 November 2014

Enhancing immune responses with immune-modulatory monoclonal antibodies (mAbs) directed to inhibitory immune-receptors is a promising modality in cancer therapy. Clinical efficacy has been demonstrated with antibodies blocking inhibitory immune checkpoints such as CTLA-4 or PD-1/PD-L1. Treatment with Ipilimumab (Yervoy®), a fully human CTLA-4 specific mAb, showed durable clinical efficacy and improved overall survival in metastatic melanoma; its mechanism(s) of action, however, are only partially understood. Recent studies in melanoma mouse models revealed that the anti-tumor activity of CTLA-4 blockade is mediated by FcgRIV-expressing macrophages in the tumor microenvironment (TME) via in-trans depletion of tumor-infiltrating regulatory T cells (Tregs). We speculated that a similar mechanism might operate in melanoma patients responding to Ipilimumab. To investigate this hypothesis, we interrogated peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding (R) and 14 non-responding (NR) to Ipilimumab. Our findings show, for the first time, that Ipilimumab leads to the depletion in vitro of Tregs via an antibody-dependent-cellular-cytotoxicity (ADCC) mechanism, selectively mediated by FcgRIIIA (CD16)-expressing, nonclassical monocytes (CD14+CD16++). In contrast, classical CD14++CD16- monocytes, lacking the FcgRIIIA expression, are unable to deplete Tregs in an ADCC assay. Interestingly, patients responding to Ipilimumab displayed significantly higher baseline peripheral frequencies of nonclassical monocytes than nonresponder patients. Evaluation of matched melanoma metastases from pre- and post-Ipilimumab time-points by IHC revealed that, in the TME, responders had the highest CD68+/CD163+ macrophage ratios at baseline, and showed decreased infiltration of Tregs after treatment. Notably, baseline Treg infiltration was comparable between the two groups. Our findings provide novel mechanistic insight into the clinical activity of Ipilimumab, highlighting the contribution of host-dependent factors into the final outcome of antibody-based immune-modulatory therapies and identify nonclassical monocytes as a potential biomarker of response.

Consent

Written informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.

Authors’ Affiliations

(1)
Department of Oncology, CHUV Service of Oncology and Ludwig Cancer Research Center
(2)
CHUV, Department of Oncology
(3)
Department of Oncology, Ludwig Cancer Research Center
(4)
Department of Oncology, CHUV and Ludwig Cancer Research Center
(5)
Institute of Social and Preventive Medicine (IUMSP)
(6)
Division of Dermatooncology, Dept. of Dermatology, University Medical Center
(7)
Ludwig Cancer Research Center

Copyright

© Romano et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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