Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells.
Targeting LAG-3 and PD-1 to Enhance T Cell Activation by Antigen-Presenting Cells.
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DOI：
10.3389/fimmu.2018.00385
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发表时间：
2018
影响因子：
7.3
通讯作者：
Subklewe M
中科院分区：
文献类型：
--
作者：
Lichtenegger FS;Rothe M;Schnorfeil FM;Deiser K;Krupka C;Augsberger C;Schlüter M;Neitz J;Subklewe M
免疫检查点抑制已被证明可以成功地重新激活针对肿瘤相关抗原的内源性T细胞应答，从而显著延长各种肿瘤实体患者的总生存期。对于具有低内源性免疫应答的恶性肿瘤，这种方法迄今尚未显示出明确的临床益处。治疗性疫苗接种，特别是树突状细胞（DC）疫苗接种，是诱导T细胞应答的策略。DC和T细胞的相互作用依赖于各种免疫检查点的受体-配体相互作用。在这项研究中，我们分析了针对程序性细胞死亡蛋白1（PD-1），HVEM，CD 244，TIM-3和淋巴细胞活化基因3（LAG-3）的阻断抗体对自体TLR成熟DC刺激后T细胞增殖和细胞因子分泌的影响。在这种情况下，我们发现LAG-3阻断导致与抑制其他途径（包括PD-1/PD-L1）相比上级T细胞活化。该结果在测量T细胞刺激（增殖、IFN-γ分泌）、各种刺激性抗原（病毒和细菌肽库、特异性病毒抗原、特异性肿瘤抗原）的不同方法中是一致的，并且在CD 4+和CD 8 + T细胞中均观察到。仅在具有弱抗原刺激的条件下，特别是当将外周血单核细胞的抗原呈递与低浓度的肽组合时，我们观察到LAG-3和PD-1阻断的双重阻断的最高T细胞刺激。我们得出结论，新的免疫反应的引发可以通过LAG-3的阻断或LAG-3和PD-1的双重阻断来强烈增强，这取决于抗原刺激的强度。
Immune checkpoint inhibition has been shown to successfully reactivate endogenous T cell responses directed against tumor-associated antigens, resulting in significantly prolonged overall survival in patients with various tumor entities. For malignancies with low endogenous immune responses, this approach has not shown a clear clinical benefit so far. Therapeutic vaccination, particularly dendritic cell (DC) vaccination, is a strategy to induce T cell responses. Interaction of DCs and T cells is dependent on receptor–ligand interactions of various immune checkpoints. In this study, we analyzed the influence of blocking antibodies targeting programmed cell death protein 1 (PD-1), HVEM, CD244, TIM-3, and lymphocyte activation gene 3 (LAG-3) on the proliferation and cytokine secretion of T cells after stimulation with autologous TLR-matured DCs. In this context, we found that LAG-3 blockade resulted in superior T cell activation compared to inhibition of other pathways, including PD-1/PD-L1. This result was consistent across different methods to measure T cell stimulation (proliferation, IFN-γ secretion), various stimulatory antigens (viral and bacterial peptide pool, specific viral antigen, specific tumor antigen), and seen for both CD4+ and CD8+ T cells. Only under conditions with a weak antigenic stimulus, particularly when combining antigen presentation by peripheral blood mononuclear cells with low concentrations of peptides, we observed the highest T cell stimulation with dual blockade of LAG-3 and PD-1 blockade. We conclude that priming of novel immune responses can be strongly enhanced by blockade of LAG-3 or dual blockade of LAG-3 and PD-1, depending on the strength of the antigenic stimulus.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
DOI：
10.1084/jem.176.2.327
发表时间：
1992-08-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Baixeras E;Huard B;Miossec C;Jitsukawa S;Martin M;Hercend T;Auffray C;Triebel F;Piatier-Tonneau D
通讯作者：
Piatier-Tonneau D
影响因子：
3.7
作者：
Lichtenegger FS;Mueller K;Otte B;Beck B;Hiddemann W;Schendel DJ;Subklewe M
通讯作者：
Subklewe M
影响因子：
7.2
作者：
Flies, Dallas B.;Higuchi, Tomoe;Adams, Sarah F.
通讯作者：
Adams, Sarah F.
影响因子：
64.8
作者：
Sahin, Ugur;Derhovanessian, Evelyna;Tuereci, Oezlem
通讯作者：
Tuereci, Oezlem