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Soluble Human LAG-3 Molecule Amplifies the In vitro Generation of Type 1 Tumor-Specific Immunity

Units of ¹ Immunotherapy of Human Tumors and ² Immunohematology, Istituto Nazionale Tumori, Milan, Italy and ³ Immutep S.A., Faculté de Pharmacie, Châtenay-Malabry, France

Requests for reprints: Giorgio Parmiani, Unit of Immunotherapy of Human Tumors, Department of Experimental Oncology, Istituto Nazionale Tumori, via G. Venezian 1, 20133 Milan, Italy. Phone: 39-02-2390-2328; Fax: 39-02-2390-2630; E-mail: giorgio.parmiani{at}istitutotumori.mi.it.

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. (Cancer Res 2006; 66(8): 4450-60)

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