PDF(Pubmed)
Abstract：
UNASSIGNED: The immune checkpoint receptor lymphocyte-activation gene 3 (LAG3) is a new target for immune checkpoint blockade (ICB), but the effects of LAG3 on atherosclerosis are not known.
UNASSIGNED: The aim of the study was to evaluate the role of LAG3 on plaque inflammation using murine hypercholesterolemic models of atherosclerosis.
UNASSIGNED: To study the role of LAG3 in atherosclerosis, we investigated both bone marrow chimeras lacking LAG3 in hematopoietic cells as well as global Lag3 -/- knockout mice. Effects of anti-LAG3 monoclonal antibody monotherapy and combination therapy with anti-programmed cell death protein 1 (PD-1) were tested in hypercholesterolemic low-density lipoprotein receptor knockout (Ldlr -/- ) mice and evaluated by histology and flow cytometry.
UNASSIGNED: LAG3-deficiency or treatment with blocking anti-LAG3 monoclonal antibodies led to increased levels of both interferon gamma-producing T helper 1 cells and effector/memory T cells, balanced by increased levels of regulatory T cells. Plaque size was affected by neither LAG3 deficiency nor LAG3 blockade, although density of T cells in plaques was 2-fold increased by loss of LAG3. Combination therapy of anti-PD-1 and anti-LAG3 had an additive effect on T cell activation and cytokine production and promoted plaque infiltration of T cells.
UNASSIGNED: Loss of LAG3 function promoted T cell activation and accumulation in plaques while not affecting plaque burden. Our report supports further clinical studies investigating cardiovascular risk in patients treated with anti-LAG3 ICB.
UNASSIGNED: The aim of the study was to evaluate the role of LAG3 on plaque inflammation using murine hypercholesterolemic models of atherosclerosis.
UNASSIGNED: To study the role of LAG3 in atherosclerosis, we investigated both bone marrow chimeras lacking LAG3 in hematopoietic cells as well as global Lag3 -/- knockout mice. Effects of anti-LAG3 monoclonal antibody monotherapy and combination therapy with anti-programmed cell death protein 1 (PD-1) were tested in hypercholesterolemic low-density lipoprotein receptor knockout (Ldlr -/- ) mice and evaluated by histology and flow cytometry.
UNASSIGNED: LAG3-deficiency or treatment with blocking anti-LAG3 monoclonal antibodies led to increased levels of both interferon gamma-producing T helper 1 cells and effector/memory T cells, balanced by increased levels of regulatory T cells. Plaque size was affected by neither LAG3 deficiency nor LAG3 blockade, although density of T cells in plaques was 2-fold increased by loss of LAG3. Combination therapy of anti-PD-1 and anti-LAG3 had an additive effect on T cell activation and cytokine production and promoted plaque infiltration of T cells.
UNASSIGNED: Loss of LAG3 function promoted T cell activation and accumulation in plaques while not affecting plaque burden. Our report supports further clinical studies investigating cardiovascular risk in patients treated with anti-LAG3 ICB.
摘要：
UASSIGNED：免疫检查点受体淋巴细胞激活基因3（LAG3）是免疫检查点阻断（ICB）的新靶标，但LAG3对动脉粥样硬化的影响尚不清楚。
未经证实：本研究的目的是使用小鼠动脉粥样硬化的高胆固醇血症模型评估LAG3在斑块炎症中的作用。
未经批准：为了研究LAG3在动脉粥样硬化中的作用，我们研究了造血细胞中缺乏LAG3的骨髓嵌合体以及全球Lag3-/-基因敲除小鼠。在高胆固醇血症低密度脂蛋白受体敲除（Ldlr-/-）小鼠中测试了抗LAG3单克隆抗体单一疗法和与抗程序性细胞死亡蛋白1（PD-1）的联合疗法的作用，并通过组织学和流式细胞术进行了评估。
未经证实：LAG3缺乏或阻断抗LAG3单克隆抗体治疗导致产生干扰素γ的辅助性T细胞和效应/记忆T细胞水平升高，通过增加的调节性T细胞水平平衡。斑块大小既不受LAG3缺乏也不受LAG3阻断的影响，尽管LAG3缺失导致斑块中T细胞的密度增加了2倍。抗PD-1和抗LAG3的联合治疗对T细胞活化和细胞因子产生具有累加作用,并促进T细胞的斑块浸润。
未经证实：LAG3功能的丧失促进了T细胞在斑块中的活化和积累，同时不影响斑块负荷。我们的报告支持进一步的临床研究，调查使用抗LAG3ICB治疗的患者的心血管风险。
未经证实：本研究的目的是使用小鼠动脉粥样硬化的高胆固醇血症模型评估LAG3在斑块炎症中的作用。
未经批准：为了研究LAG3在动脉粥样硬化中的作用，我们研究了造血细胞中缺乏LAG3的骨髓嵌合体以及全球Lag3-/-基因敲除小鼠。在高胆固醇血症低密度脂蛋白受体敲除（Ldlr-/-）小鼠中测试了抗LAG3单克隆抗体单一疗法和与抗程序性细胞死亡蛋白1（PD-1）的联合疗法的作用，并通过组织学和流式细胞术进行了评估。
未经证实：LAG3缺乏或阻断抗LAG3单克隆抗体治疗导致产生干扰素γ的辅助性T细胞和效应/记忆T细胞水平升高，通过增加的调节性T细胞水平平衡。斑块大小既不受LAG3缺乏也不受LAG3阻断的影响，尽管LAG3缺失导致斑块中T细胞的密度增加了2倍。抗PD-1和抗LAG3的联合治疗对T细胞活化和细胞因子产生具有累加作用,并促进T细胞的斑块浸润。
未经证实：LAG3功能的丧失促进了T细胞在斑块中的活化和积累，同时不影响斑块负荷。我们的报告支持进一步的临床研究，调查使用抗LAG3ICB治疗的患者的心血管风险。
