Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3.
Plasmacytoid dendritic cells (pDCs) at tumor sites are often tolerogenic. Although pDCs initiate innate and adaptive immunity upon Toll-like receptor (TLR) triggering by pathogens, TLR-independent signals may be responsible for pDC activation and immune suppression in the tumor inflammatory environment. To identify molecules that are potentially involved in alternative pDC activation, we explored the expression and function of lymphocyte activation gene 3 (LAG-3) in human pDCs. In this report, we showed the expression of LAG-3 on the cell surface of a subset of circulating human pDCs. LAG-3+ pDCs exhibited a partially mature phenotype and were enriched at tumor sites in samples from melanoma patients. We found that LAG-3 interacted with major histocompatibility complex class II (MHC-II) to induce TLR-independent activation of pDCs with limited IFNα and enhanced IL-6 production. This in vitro cytokine profile of LAG-3-activated pDCs paralleled that of tumor-associated pDCs analyzed ex vivo. By confocal microscopy, LAG-3+ pDCs detected in melanoma-invaded lymph nodes (LNs) stained positive for IL-6 and preferentially localized near melanoma cells. These results suggest that LAG-3-mediated activation of pDCs takes place in vivo at tumor sites, and it is in part responsible for directing an immune-suppressive environment.
Unit of Immunotherapy of Human Tumor, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Chiara
C
Camisaschi
Unit of Immunotherapy of Human Tumor, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Annamaria
A
De Filippo
Unit of Immunotherapy of Human Tumor, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Valeria
V
Beretta
Consorzio MIA (Microscopy and Image Analysis), University of Milano-Bicocca, Milan, Italy.
Barbara
B
Vergani
Consorzio MIA (Microscopy and Image Analysis), University of Milano-Bicocca, Milan, Italy.
Antonello
A
Villa
Unit of Immunotherapy of Human Tumor, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Elisabetta
E
Vergani
Melanoma and Sarcoma Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Mario
M
Santinami
Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Antonello Domenico
AD
Cabras
Immunohematology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Flavio
F
Arienti
Immutep S.A., Faculté de Pharmacie, Chatenay-Malabry, France.
Frédéric
F
Triebel
Unit of Immunotherapy of Human Tumor, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Monica
M
Rodolfo
Unit of Immunotherapy of Human Tumor, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Licia
L
Rivoltini
Unit of Immunotherapy of Human Tumor, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: chiara.castelli@istitutotumori.mi.it.
Chiara
C
Castelli
D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D019556:COS Cells; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000276:immunology; D018932:Chemokine CCL2 / Q000276:immunology / Q000378:metabolism; D002522:Chlorocebus aethiops; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology* / Q000473:pathology; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D012878:Skin Neoplasms / Q000276:immunology* / Q000473:pathology; D059016:Tumor Microenvironment / Q000276:immunology; D000093322:Lymphocyte Activation Gene 3 Protein
D015703:Antigens, CD; C111835:CCL2 protein, human; D018932:Chemokine CCL2; C508600:IL6 protein, human; D015850:Interleukin-6; D000093322:Lymphocyte Activation Gene 3 Protein