Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients.
Enhancing immune responses with immune-modulatory monoclonal antibodies 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 cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) or PD-1/PD-L1. Treatment with ipilimumab, a fully human CTLA-4-specific mAb, showed durable clinical efficacy in metastatic melanoma; its mechanism of action is, however, only partially understood. This is a study of 29 patients with advanced cutaneous melanoma treated with ipilimumab. We analyzed peripheral blood mononuclear cells (PBMCs) and matched melanoma metastases from 15 patients responding and 14 not responding to ipilimumab by multicolor flow cytometry, antibody-dependent cell-mediated cytotoxicity (ADCC) assay, and immunohistochemistry. PBMCs and matched tumor biopsies were collected 24 h before (i.e., baseline) and up to 4 wk after ipilimumab. Our findings show, to our knowledge for the first time, that ipilimumab can engage ex vivo FcγRIIIA (CD16)-expressing, nonclassical monocytes resulting in ADCC-mediated lysis of regulatory T cells (Tregs). In contrast, classical CD14(++)CD16(-) monocytes are unable to do so. Moreover, we show that patients responding to ipilimumab display significantly higher baseline peripheral frequencies of nonclassical monocytes compared with nonresponder patients. In the tumor microenvironment, responders have higher CD68(+)/CD163(+) macrophage ratios at baseline and show decreased Treg infiltration after treatment. Together, our results suggest that anti-CTLA-4 therapy may target Tregs in vivo. Larger translational studies are, however, warranted to substantiate this mechanism of action of ipilimumab in patients.
Service of Medical Oncology, Laboratory of Tumor Immunobiology, Ludwig Cancer Research Center and Department of Oncology, and emanuela.romano@chuv.ch.
Emanuela
E
Romano
Laboratory of Tumor Immunobiology.
Monika
M
Kusio-Kobialka
Ludwig Cancer Research Center and Department of Oncology, and Department of Pathology, University of Athens Medical School, 11527 Athens, Greece; and.
Periklis G
PG
Foukas
Ludwig Cancer Research Center and Department of Oncology, and.
Petra
P
Baumgaertner
Ludwig Cancer Research Center and Department of Oncology, and.
Christiane
C
Meyer
Institute of Social and Preventive Medicine, University Hospital of Lausanne, 1011 Lausanne, Switzerland; and.
Pierluigi
P
Ballabeni
Service of Medical Oncology, Ludwig Cancer Research Center and Department of Oncology, and.
Olivier
O
Michielin
Department of Dermatology, University Medical Center, 72076 Tübingen, Germany.
Benjamin
B
Weide
Ludwig Cancer Research Center and Department of Oncology, and.
Pedro
P
Romero
Ludwig Cancer Research Center and Department of Oncology, and.
Daniel E
DE
Speiser
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry; D017252:CD3 Complex / Q000378:metabolism; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D000074324:Ipilimumab; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy*; D051379:Mice; D008875:Middle Aged; D017452:Receptors, IgG / Q000378:metabolism; D012878:Skin Neoplasms / Q000097:blood / Q000188:drug therapy*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology*; D000097382:CD68 Molecule
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000970:Antineoplastic Agents; D017252:CD3 Complex; D058851:GPI-Linked Proteins; D000074324:Ipilimumab; D018950:Lipopolysaccharide Receptors; D017452:Receptors, IgG; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C428200:FCGR3B protein, human
ADCC; Tregs; ipilimumab; macrophages; monocytes