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

Casati, Chiara; Camisaschi, Chiara; Rini, Francesca; Arienti, Flavio; Rivoltini, Licia; Triebel, Frédéric; Parmiani, Giorgio; Castelli, Chiara

doi:10.1158/0008-5472.can-05-2728

Cited by 61 publications

(53 citation statements)

References 47 publications

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“…As a soluble fusion protein, LAG-3 has also been shown to bind MHC II with a much higher avidity than CD4 (27), to increase the capacity of MHC II-positive macrophages and immature dendritic cells to induce T cell responses in vitro (28), and to enhance the in vitro induction of viral and tumor-specific cytotoxic T cells (29). Accordingly, the LAG-3 fusion protein has been suggested as a potential adjuvant for cancer vaccines (29), including those for melanoma, for which most attempts at immunotherapy have met with little clinical success.…”

mentioning

confidence: 99%

MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis

Hémon

Jean-Louis

Ramgolam

et al. 2011

The Journal of Immunology

216

146

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Melanoma is the most aggressive skin cancer in humans that often expresses MHC class II (MHC II) molecules, which could make these tumors eliminable by the immune system. However, this MHC II expression has been associated with poor prognosis, and there is a lack of immune-mediated eradication. The lymphocyte activation gene-3 (LAG-3) is a natural ligand for MHC II that is substantially expressed on melanoma-infiltrating T cells including those endowed with potent immune-suppressive activity. Based on our previous data showing the signaling capacity of MHC II in melanoma cells, we hypothesized that LAG-3 could contribute to melanoma survival through its MHC II signaling capacity in melanoma cells. In this study, we demonstrate that both soluble LAG-3 and LAG-3–transfected cells can protect MHC II-positive melanoma cells, but not MHC II-negative cells, from FAS-mediated and drug-induced apoptosis. Interaction of LAG-3 with MHC II expressed on melanoma cells upregulates both MAPK/Erk and PI3K/Akt pathways, albeit with different kinetics. Inhibition studies using specific inhibitors of both pathways provided evidence of their involvement in the LAG-3–induced protection from apoptosis. Altogether, our data suggest that the LAG-3–MHC II interaction could be viewed as a bidirectional immune escape pathway in melanoma, with direct consequences shared by both melanoma and immune cells. In the future, compounds that efficiently hinder LAG-3–MHC II interaction might be used as an adjuvant to current therapy for MHC II-positive melanoma.

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confidence: 99%

MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis

Hémon

Jean-Louis

Ramgolam

et al. 2011

The Journal of Immunology

216

146

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“…A sequences of the T-cell responses to HBsAg. It is possible to explain approximately 5-10% of healthy vaccine recipients fail to produce protective levels of antibodies to the hepatitis B vaccine after standard immunization [28][29][30][31][32] . Although confirming the conclusion is challenging, there are 3 possible factors link to the phenomenon: the happen of the events by chance (because only 15 patients with PRSS1 gene mutation were researched), the patient's human leukocyte antigen genetype and the incongruent immune response to the vaccine components [33] .…”

Section: Discussionmentioning

confidence: 99%

The Use of Artificial Neural Networks in Analysis Cationic Trypsinogen Gene and Hepatitis B Surface Antigen

Liu¹,

Kai²,

Zehao³

et al. 2009

American J. of Immunology

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Problem statement: More and more severe hepatitis cases reported in China are infected with HBV and the immune response of HBV will be reduced if mutations occur in the TCR, therefore it is very important to investigate the relation of T-cellular function and clinical effect by studying the function of T-cell receptor. Approach: Artificial Neural Networks (ANN) was applied to analyze basic data (the three structural of HBsAg, the ligand of HBsAg and the clinical immunological characterizations, the laboratory data, the genetypes of cationic trypsinogen gene (PRSS1) derived from 78 patients with pancreatitis and 60 normal controls were also collected. What is more, we used T-cell culture with HBV and flow cytometry to check the result of ANN predict. To examine the characteristics of T-cells capable of coexisting with the secreted HBsAg, T-cell receptor from A121T, C139S, silent mutation and normal PRSS1 gene in the patients with pancreatitis were put into research. To ensure that PRSS1 gene would affect HBsAg-specific T-cells receptor, we compared the rate of multiplication and CD4/CD8 of T-cell after culture with HBV at 0H, 12H, 24H, 36H, 48H and 72H time point. Results: The protein's structural predicted by the ANN could specifically explain the phenomenon that the turbulence and different of anti-HBs lever of the patients with pancreatitis. The three-dimensional of the protein that consist with PRSS1 gene would accord with HBsAg. It may be one of the HBsAg-specific T-cell receptor. Result of T-cell culture also showed that different genetypes of PRSS1 had different results. In the T-cell proliferation, the groups of PRSS1 mutation (A121T and C139S) were significant lower than the group of silent mutation and normal controls and it was the same to the result of CD4/CD8. Conclusion: The ANN had been integrated into a previously published comprehensive web server to support immunology analysis and the PRSS1 gene may be the unit for HBsAg immune response.

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“…In this setting, APC of PBMC exposed in vitro to peptide and hLAG-3Ig displayed a more mature phenotype than APC of PBMC exposed to peptide only, suggesting that the hLAG-3Ig adjuvant effect could have been dependent on activation of circulating APC (14). To evaluate whether hLAG-3Ig worked by a direct mechanism in the induction of DC maturation, iMoDC (100% CD11c ϩ and CD1a ϩ , data not shown) were matured with hLAG-3Ig and assessed for their phenotype.…”

Section: Soluble Hlag-3ig Recombinant Protein Induces Phenotypic Matumentioning

confidence: 91%

“…Several data have been reported on the ability of human rLAG-3 protein (hLAG-3Ig) to work as an adjuvant in in vivo mouse model (12, 13) and we and others have recently showed that soluble rhLAG-3Ig is able to enhance the in vitro induction of viral-and tumor-specific CTL in humans (14,15).…”

mentioning

confidence: 99%

Human Lymphocyte Activation Gene-3 Molecules Expressed by Activated T Cells Deliver Costimulation Signal for Dendritic Cell Activation

Casati¹,

Camisaschi²,

Novellino³

et al. 2008

The Journal of Immunology

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Data have been reported on the in vivo adjuvant role of soluble lymphocyte activation gene-3 (LAG-3) recombinant protein in mouse models and on its ability to support the in vitro generation of human, tumor-specific CTLs. In this study, we show that soluble human rLAG-3 protein (hLAG-3Ig) used in vitro as a single maturation agent induces phenotypic maturation of monocyte-derived dendritic cells and promoted the production of chemokines and TNF-α inflammatory cytokine. When given in association with optimal or suboptimal doses of CD40/CD40L, hLAG-3Ig functions as a strong costimulatory factor and induces full functional activation of monocyte-derived dendritic cells that includes the production of high level of IL-12p70. Moreover, evidence is here provided that this costimulatory function licensing dendritic cells to produce IL-12p70 is also a functional property of LAG-3 molecules when expressed in a physiological context by CD4+ activated T cells. Altogether, these data show for the first time a role of LAG-3 in mediating dendritic cell activation when expressed on the T cell surface or released after specific Ag stimulation in the interspaces of immunological synapses.

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Soluble Human LAG-3 Molecule Amplifies theIn vitroGeneration of Type 1 Tumor-Specific Immunity

Cited by 61 publications

References 47 publications

MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis

MHC Class II Engagement by Its Ligand LAG-3 (CD223) Contributes to Melanoma Resistance to Apoptosis

The Use of Artificial Neural Networks in Analysis Cationic Trypsinogen Gene and Hepatitis B Surface Antigen

Human Lymphocyte Activation Gene-3 Molecules Expressed by Activated T Cells Deliver Costimulation Signal for Dendritic Cell Activation

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