A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors

Triebel, Frédéric; Hacène, K.; Pichon, M.

doi:10.1016/j.canlet.2005.04.015

Cited by 89 publications

(68 citation statements)

References 23 publications

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“…In large series of patients, high levels of serum sLAG-3 have been shown to be associated with resistance to tuberculosis, a disease where Th1 responses are crucial in defense against Mycobacteria (15). Finally, studying patients' sera collected at the time of first diagnosis for breast cancer, we found that both disease-free and overall survival rates at 10 years were higher in patients who had higher levels of sLAG-3 at diagnosis (16).…”

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confidence: 77%

A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells

Brignone

Grygar

Marcu

et al. 2007

The Journal of Immunology

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The principal antitumor immune response is mediated through the activation of type 1 cytotoxic (Tc1) CD8 T cells, NK cells, and monocytes/macrophages. In this study, we investigated the potency of a clinical-grade soluble form of lymphocyte activation gene-3 protein (IMP321), a physiological high-affinity MHC class II binder, at inducing in PBMCs an appropriate cytotoxic-type response in short-term ex vivo assays. We found that IMP321 binds to a minority (<10%) of MHC class II + cells in PBMCs, including all myeloid dendritic cells, and a small fraction of monocytes. Four hours after addition of IMP321 to PBMCs, these myeloid cells produce TNF-α and CCL4 as determined by intracellular staining. At 18 h, 1% of CD8+ T cells and 3.7% NK cells produce Tc1 cytokines such as IFN-γ and/or TNF-α (mean values from 60 blood donors). Similar induction was observed in metastatic cancer patient PBMCs, but the values were lower for the NK cell subset. Early APC activation by IMP321 is needed for this Tc1-type activation because pure sorted CD8+ T cells could not be activated by IMP321. Only Ag-experienced, fully differentiated granzyme+ CD8 T cells (effector and effector memory but not naive or central memory T cells) are induced by IMP321 to full Tc1 activation. In contrast to IMP321, TLR1-9 agonists induce IL-10 and are therefore unable to induce this Tc1 IFN-γ+ response. Thus, IMP321 has many properties that confirm its potential to be a new class of immunopotentiator in cancer patients.

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confidence: 77%

A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells

Brignone

Grygar

Marcu

et al. 2007

The Journal of Immunology

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“…Moreover, in patients, the level of natural soluble LAG-3 in sera is associated with a cellular immune response, and high levels seemed to be protective in conditions where Th1 responses are an essential component of immune protection, such as tuberculosis or cancer (21,50).…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies in mice (15,16) and in humans (17) reported that LAG-3 negatively regulates T-cell function and homeostasis. However, as a soluble molecule, LAG-3 activates antigen-presenting cells (APC) through MHC class II signaling (18,19), leading to increased antigenspecific T-cell responses in vivo (20), and its presence as free molecule in the sera of subgroups of breast cancer patients at diagnosis has been correlated with a better survival (21). Given these critical roles of the protein in the immune system, its physiologic expression in human tumor-infiltrating lymphocytes (22) and its ability to activate APCs in vitro, soluble LAG-3 molecule has been exploited as a vaccine adjuvant in in vivo mouse models, by using either viral-associated antigens or TAAs given as irradiated LAG-3-transfected syngeneic tumor cells, soluble proteins, or as gene-encoding plasmids (20,23,24).…”

Section: Introductionmentioning

confidence: 99%

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

Casati¹,

Camisaschi²,

Rini³

et al. 2006

Cancer Research

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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 tumorassociated, 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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“…In vitro and in vivo murine studies have suggested that plasma can also limit T cell activation and homeostasis by binding to MHC class II on antigen-presenting cells (13). Importantly, a few clinical studies have shown associations between plasma LAG3 and tuberculosis resistance (14) and breast cancer prognosis (15).…”

Section: Introductionmentioning

confidence: 99%

Lymphocyte activation gene 3 and coronary artery disease

et al. 2016

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BACKGROUND:The lipoprotein scavenger receptor BI (SCARB1) rs10846744 noncoding variant is significantly associated with atherosclerotic disease independently of traditional cardiovascular risk factors. We identified a potentially novel connection between rs10846744, the immune checkpoint inhibitor lymphocyte activation gene 3 (LAG3), and atherosclerosis. METHODS:In vitro approaches included flow cytometry, lipid raft isolation, phosphosignaling, cytokine measurements, and overexpressing and silencing LAG3 protein. Fasting plasma LAG3 protein was measured in hyperalphalipoproteinemic (HALP) and Multi-Ethnic Study of Atherosclerosis (MESA) participants. RESULTS:In comparison with rs10846744 reference (GG homozygous) cells, LAG3 protein levels by flow cytometry (P < 0.001), in lipid rafts stimulated and unstimulated (P = 0.03), and phosphosignaling downstream of B cell receptor engagement of CD79A (P = 0.04), CD19 (P = 0.04), and LYN (P = 0.001) were lower in rs10846744 risk (CC homozygous) cells. Overexpressing LAG3 protein in risk cells and silencing LAG3 in reference cells confirmed its importance in phosphosignaling. Secretion of TNF-α was higher (P = 0.04) and IL-10 was lower (P = 0.04) in risk cells. Plasma LAG3 levels were lower in HALP carriers of the CC allele (P < 0.0001) and by race (P = 0.004). In MESA, race (P = 0.0005), age (P = 0.003), lipid medications (P = 0.03), smoking history (P < 0.0001), and rs10846744 genotype (P = 0.002) were independent predictors of plasma LAG3. In multivariable regression models, plasma LAG3 was significantly associated with HDL-cholesterol (HDL-C) (P = 0.007), plasma IL-10 (P < 0.0001), and provided additional predictive value above the Framingham risk score (P = 0.04). In MESA, when stratified by high HDL-C, plasma LAG3 was associated with coronary heart disease (CHD) (odds ratio 1.45, P = 0.004).CONCLUSION: Plasma LAG3 is a potentially novel independent predictor of HDL-C levels and CHD risk.

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A soluble lymphocyte activation gene-3 (sLAG-3) protein as a prognostic factor in human breast cancer expressing estrogen or progesterone receptors

Cited by 89 publications

References 23 publications

A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells

A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells

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

Lymphocyte activation gene 3 and coronary artery disease

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