title: Soluble human LAG-3 molecule amplifies the in vitro generation of type 1 tumor-specific immunity.
abstract: The adjuvant activities of the human lymphocyte activation gene-3 (LAG-3) molecule have been evaluated in a human setting by investigating the ability of a soluble recombinant human LAG-3 protein (hLAG-3Ig) to enhance the in vitro induction of viral- and tumor-specific CTLs. We found that soluble human LAG-3 significantly sustained the generation and expansion of influenza matrix protein Melan-A/MART-1 and survivin-specific CD8+ T lymphocytes in peripheral blood mononuclear cells (PBMC) of both cancer patients and healthy donors, showing its ability to boost CD8+ T-cell memory response or to prime naive T cells in vitro. The peptide-specific T cells generated in the presence of hLAG-3Ig were endowed with cytotoxic activity and enhanced release of type 1 cytotoxic T (Tc1) cytokines and were able to recognize tumor cells expressing their nominal antigen. Phenotype and cytokine/chemokines produced by antigen-presenting cells (APC) of PBMCs exposed in vitro for 2 days to peptide and hLAG-3Ig indicate that the LAG-3-mediated adjuvant effect may depend on a direct activation of circulating APCs. Our data revealed the activity of hLAG-3Ig in inducing tumor-associated, antigen-specific CD8+ T-cell responses in a human setting and strongly support the conclusion that this recombinant protein is a potential candidate adjuvant for cancer vaccines.
authors.affiliation: Unit of Immunotherapy of Human Tumors, Istituto Nazionale Tumori, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Casati
authors.forename: Chiara
authors.initials: C
authors.lastname: Camisaschi
authors.forename: Francesca
authors.initials: F
authors.lastname: Rini
authors.forename: Flavio
authors.initials: F
authors.lastname: Arienti
authors.forename: Licia
authors.initials: L
authors.lastname: Rivoltini
authors.forename: Frédéric
authors.initials: F
authors.lastname: Triebel
authors.forename: Giorgio
authors.initials: G
authors.lastname: Parmiani
authors.forename: Chiara
authors.initials: C
authors.lastname: Castelli
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology*; D000951:Antigens, Neoplasm; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016466:CHO Cells; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000628:therapy; D006224:Cricetinae; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D009363:Neoplasm Proteins / Q000276:immunology; D010455:Peptides / Q000138:chemical synthesis / Q000276:immunology; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; D000951:Antigens, Neoplasm; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007074:Immunoglobulin G; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D010455:Peptides; D011994:Recombinant Proteins; D007371:Interferon-gamma; D000093322:Lymphocyte Activation Gene 3 Protein