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Abstract：
BACKGROUND: Immunotherapy has revolutionized cancer treatment. However, immune checkpoint inhibitors (ICIs) that target PD-1 (programmed cell death protein-1) and/or CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) are commonly associated with acute immune-related adverse events. Accumulating evidence also suggests that ICIs aggravate existing inflammatory diseases.
OBJECTIVE: As inflammation drives atherosclerotic cardiovascular disease, we studied the propensity of short-term ICI therapy to aggravate atherosclerosis.
METHODS: We used 18F-FDG (2-deoxy-2-[fluorine-18]fluoro-D-glucose) positron emission tomography-computed tomography to detect macrophage-driven vascular and systemic inflammation in pembrolizumab and nivolumab/ipilimumab-treated melanoma patients. In parallel, atherosclerotic Ldlr -/- mice were treated with CTLA-4 and PD-1 inhibition to study the proinflammatory consequences of immune checkpoint inhibition.
RESULTS: ICI treatment did not affect 18F-FDG uptake in the large arteries, spleen, and bone marrow of melanoma patients, nor myeloid cell activation in blood and lymphoid organs in hyperlipidemic mice. In contrast, we found marked changes in the adaptive immune response (i.e., increased CD4+ effector T cell and CD8+ cytotoxic T cell numbers in lymphoid organs and the arterial wall of our hyperlipidemic mice). Although plaque size was unaffected, plaques had progressed toward a lymphoid-based inflammatory phenotype, characterized by a 2.7-fold increase of CD8+ T cells and a 3.9-fold increase in necrotic core size. Increased endothelial activation was observed with a 2.2-fold and 1.6-fold increase in vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, respectively.
CONCLUSIONS: This study demonstrates that combination therapy with anti-CTLA-4 and anti-PD-1 antibodies does not affect myeloid-driven vascular and systemic inflammation in melanoma patients and hyperlipidemic mice. However, short-term ICI therapy in mice induces T cell-mediated plaque inflammation and drives plaque progression.
OBJECTIVE: As inflammation drives atherosclerotic cardiovascular disease, we studied the propensity of short-term ICI therapy to aggravate atherosclerosis.
METHODS: We used 18F-FDG (2-deoxy-2-[fluorine-18]fluoro-D-glucose) positron emission tomography-computed tomography to detect macrophage-driven vascular and systemic inflammation in pembrolizumab and nivolumab/ipilimumab-treated melanoma patients. In parallel, atherosclerotic Ldlr -/- mice were treated with CTLA-4 and PD-1 inhibition to study the proinflammatory consequences of immune checkpoint inhibition.
RESULTS: ICI treatment did not affect 18F-FDG uptake in the large arteries, spleen, and bone marrow of melanoma patients, nor myeloid cell activation in blood and lymphoid organs in hyperlipidemic mice. In contrast, we found marked changes in the adaptive immune response (i.e., increased CD4+ effector T cell and CD8+ cytotoxic T cell numbers in lymphoid organs and the arterial wall of our hyperlipidemic mice). Although plaque size was unaffected, plaques had progressed toward a lymphoid-based inflammatory phenotype, characterized by a 2.7-fold increase of CD8+ T cells and a 3.9-fold increase in necrotic core size. Increased endothelial activation was observed with a 2.2-fold and 1.6-fold increase in vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, respectively.
CONCLUSIONS: This study demonstrates that combination therapy with anti-CTLA-4 and anti-PD-1 antibodies does not affect myeloid-driven vascular and systemic inflammation in melanoma patients and hyperlipidemic mice. However, short-term ICI therapy in mice induces T cell-mediated plaque inflammation and drives plaque progression.
摘要：
背景：免疫疗法彻底改变了癌症治疗。然而,靶向PD-1(程序性细胞死亡蛋白-1)和/或CTLA-4(细胞毒性T淋巴细胞相关抗原-4)的免疫检查点抑制剂(ICI)通常与急性免疫相关不良事件相关.越来越多的证据还表明，ICI加重了现有的炎症性疾病。
目的：由于炎症导致动脉粥样硬化性心血管疾病，我们研究了短期ICI治疗加重动脉粥样硬化的倾向.
方法：我们使用18F-FDG（2-脱氧-2-[氟-18]氟-D-葡萄糖）正电子发射断层扫描-计算机断层扫描来检测派姆单抗和纳武单抗/伊匹单抗治疗的黑色素瘤患者的巨噬细胞驱动的血管和全身炎症。并行,用CTLA-4和PD-1抑制剂治疗动脉粥样硬化Ldlr-/-小鼠，以研究免疫检查点抑制的促炎后果。
结果：ICI治疗不影响大动脉中18F-FDG的摄取，脾,脾黑色素瘤患者的骨髓，高脂血症小鼠血液和淋巴器官中的骨髓细胞活化。相比之下,我们发现适应性免疫反应发生了显著变化(即，我们的高脂血症小鼠的淋巴器官和动脉壁中CD4效应T细胞和CD8细胞毒性T细胞数量增加）。尽管斑块大小未受影响，斑块已经发展为基于淋巴的炎症表型，以CD8+T细胞增加2.7倍和坏死核心大小增加3.9倍为特征。观察到内皮活化增加，血管细胞粘附分子-1和细胞间粘附分子-1分别增加2.2倍和1.6倍。
结论：这项研究表明，抗CTLA-4和抗PD-1抗体的联合治疗不会影响黑色素瘤患者和高脂血症小鼠的骨髓驱动的血管和全身性炎症。然而,小鼠短期ICI治疗诱导T细胞介导的斑块炎症并驱动斑块进展。
目的：由于炎症导致动脉粥样硬化性心血管疾病，我们研究了短期ICI治疗加重动脉粥样硬化的倾向.
方法：我们使用18F-FDG（2-脱氧-2-[氟-18]氟-D-葡萄糖）正电子发射断层扫描-计算机断层扫描来检测派姆单抗和纳武单抗/伊匹单抗治疗的黑色素瘤患者的巨噬细胞驱动的血管和全身炎症。并行,用CTLA-4和PD-1抑制剂治疗动脉粥样硬化Ldlr-/-小鼠，以研究免疫检查点抑制的促炎后果。
结果：ICI治疗不影响大动脉中18F-FDG的摄取，脾,脾黑色素瘤患者的骨髓，高脂血症小鼠血液和淋巴器官中的骨髓细胞活化。相比之下,我们发现适应性免疫反应发生了显著变化(即，我们的高脂血症小鼠的淋巴器官和动脉壁中CD4效应T细胞和CD8细胞毒性T细胞数量增加）。尽管斑块大小未受影响，斑块已经发展为基于淋巴的炎症表型，以CD8+T细胞增加2.7倍和坏死核心大小增加3.9倍为特征。观察到内皮活化增加，血管细胞粘附分子-1和细胞间粘附分子-1分别增加2.2倍和1.6倍。
结论：这项研究表明，抗CTLA-4和抗PD-1抗体的联合治疗不会影响黑色素瘤患者和高脂血症小鼠的骨髓驱动的血管和全身性炎症。然而,小鼠短期ICI治疗诱导T细胞介导的斑块炎症并驱动斑块进展。
