PDF(Pubmed)
Abstract：
Because prior immune checkpoint inhibitor (ICI) therapy in cancer patients presenting with COVID-19 may affect outcomes, we investigated the beta-coronavirus, murine hepatitis virus (MHV)-1, in a lethal pneumonia model in the absence (Study 1) or presence of prior programmed cell death ligand-1 (PD-L1) antibody (PD-L1mAb) treatment (Study 2).
In Study 1, animals were inoculated intratracheally with MHV-1 or vehicle and evaluated at day 2, 5, and 10 after infection. In Study 2, uninfected or MHV-1-infected animals were pretreated intraperitoneally with control or PD-L1-blocking antibodies (PD-L1mAb) and evaluated at day 2 and 5 after infection. Each study examined survival, physiologic and histologic parameters, viral titers, lung immunophenotypes, and mediator production.
Study 1 results recapitulated the pathogenesis of COVID-19 and revealed increased cell surface expression of checkpoint molecules (PD-L1, PD-1), higher expression of the immune activation marker angiotensin converting enzyme (ACE), but reduced detection of the MHV-1 receptor CD66a on immune cells in the lung, liver, and spleen. In addition to reduced detection of PD-L1 on all immune cells assayed, PD-L1 blockade was associated with increased cell surface expression of PD-1 and ACE, decreased cell surface detection of CD66a, and improved oxygen saturation despite reduced blood glucose levels and increased signs of tissue hypoxia. In the lung, PD-L1mAb promoted S100A9 but inhibited ACE2 production concomitantly with pAKT activation and reduced FOXO1 levels. PD-L1mAb promoted interferon-γ but inhibited IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production, contributing to reduced bronchoalveolar lavage levels of eosinophils and neutrophils. In the liver, PD-L1mAb increased viral clearance in association with increased macrophage and lymphocyte recruitment and liver injury. PD-L1mAb increased the production of virally induced mediators of injury, angiogenesis, and neuronal activity that may play role in COVID-19 and ICI-related neurotoxicity. PD-L1mAb did not affect survival in this murine model.
In Study 1 and Study 2, ACE was upregulated and CD66a and ACE2 were downregulated by either MHV-1 or PD-L1mAb. CD66a is not only the MHV-1 receptor but also an identified immune checkpoint and a negative regulator of ACE. Crosstalk between CD66a and PD-L1 or ACE/ACE2 may provide insight into ICI therapies. These networks may also play role in the increased production of S100A9 and neurological mediators in response to MHV-1 and/or PD-L1mAb, which warrant further study. Overall, these findings support observational data suggesting that prior ICI treatment does not alter survival in patients presenting with COVID-19.
In Study 1, animals were inoculated intratracheally with MHV-1 or vehicle and evaluated at day 2, 5, and 10 after infection. In Study 2, uninfected or MHV-1-infected animals were pretreated intraperitoneally with control or PD-L1-blocking antibodies (PD-L1mAb) and evaluated at day 2 and 5 after infection. Each study examined survival, physiologic and histologic parameters, viral titers, lung immunophenotypes, and mediator production.
Study 1 results recapitulated the pathogenesis of COVID-19 and revealed increased cell surface expression of checkpoint molecules (PD-L1, PD-1), higher expression of the immune activation marker angiotensin converting enzyme (ACE), but reduced detection of the MHV-1 receptor CD66a on immune cells in the lung, liver, and spleen. In addition to reduced detection of PD-L1 on all immune cells assayed, PD-L1 blockade was associated with increased cell surface expression of PD-1 and ACE, decreased cell surface detection of CD66a, and improved oxygen saturation despite reduced blood glucose levels and increased signs of tissue hypoxia. In the lung, PD-L1mAb promoted S100A9 but inhibited ACE2 production concomitantly with pAKT activation and reduced FOXO1 levels. PD-L1mAb promoted interferon-γ but inhibited IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) production, contributing to reduced bronchoalveolar lavage levels of eosinophils and neutrophils. In the liver, PD-L1mAb increased viral clearance in association with increased macrophage and lymphocyte recruitment and liver injury. PD-L1mAb increased the production of virally induced mediators of injury, angiogenesis, and neuronal activity that may play role in COVID-19 and ICI-related neurotoxicity. PD-L1mAb did not affect survival in this murine model.
In Study 1 and Study 2, ACE was upregulated and CD66a and ACE2 were downregulated by either MHV-1 or PD-L1mAb. CD66a is not only the MHV-1 receptor but also an identified immune checkpoint and a negative regulator of ACE. Crosstalk between CD66a and PD-L1 or ACE/ACE2 may provide insight into ICI therapies. These networks may also play role in the increased production of S100A9 and neurological mediators in response to MHV-1 and/or PD-L1mAb, which warrant further study. Overall, these findings support observational data suggesting that prior ICI treatment does not alter survival in patients presenting with COVID-19.
摘要：
■因为先前对患有COVID-19的癌症患者进行免疫检查点抑制剂（ICI）治疗可能会影响预后，我们调查了β-冠状病毒,小鼠肝炎病毒（MHV）-1，在不存在（研究1）或存在先前程序性细胞死亡配体-1（PD-L1）抗体（PD-L1mAb）治疗（研究2）的致死性肺炎模型中。
在研究1中,用MHV-1或载体对动物进行气管内接种,并在感染后第2、5和10天进行评价。在研究2中，未感染或MHV-1感染的动物用对照或PD-L1阻断抗体（PD-L1mAb）腹膜内预处理，并在感染后第2天和第5天进行评估。每项研究都检查了生存率，生理和组织学参数，病毒滴度,肺免疫表型，和中介生产。
■研究1结果概括了COVID-19的发病机制，并显示检查点分子（PD-L1，PD-1）的细胞表面表达增加，免疫激活标记物血管紧张素转换酶（ACE）的高表达，但是减少了MHV-1受体CD66a在肺免疫细胞上的检测，肝脏,还有脾脏.除了在所有测定的免疫细胞上减少PD-L1的检测，PD-L1阻断与PD-1和ACE的细胞表面表达增加有关，CD66a的细胞表面检测减少，尽管血糖水平降低，组织缺氧迹象增加，但氧饱和度改善。在肺部，PD-L1mAb促进S100A9，但抑制ACE2的产生同时pAKT激活和降低FOXO1水平。PD-L1mAb促进干扰素-γ，但抑制IL-5和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的产生，有助于降低支气管肺泡灌洗水平的嗜酸性粒细胞和嗜中性粒细胞。在肝脏中，PD-L1mAb增加与巨噬细胞和淋巴细胞募集和肝损伤相关的病毒清除率。PD-L1mAb增加了病毒诱导的损伤介质的产生，血管生成,和可能在COVID-19和ICI相关神经毒性中起作用的神经元活性。PD-L1mAb不影响该鼠模型中的存活。
■在研究1和研究2中，ACE被MHV-1或PD-L1mAb上调，CD66a和ACE2被下调。CD66a不仅是MHV-1受体，而且是公认的免疫检查点和ACE的负调节因子。CD66a和PD-L1或ACE/ACE2之间的串扰可以提供对ICI治疗的见解。这些网络也可能在响应MHV-1和/或PD-L1mAb的S100A9和神经介质的增加产生中起作用。这需要进一步研究。总的来说,这些发现支持了观察性数据,这些数据表明,在出现COVID-19的患者中,先前的ICI治疗并没有改变生存率.
在研究1中,用MHV-1或载体对动物进行气管内接种,并在感染后第2、5和10天进行评价。在研究2中，未感染或MHV-1感染的动物用对照或PD-L1阻断抗体（PD-L1mAb）腹膜内预处理，并在感染后第2天和第5天进行评估。每项研究都检查了生存率，生理和组织学参数，病毒滴度,肺免疫表型，和中介生产。
■研究1结果概括了COVID-19的发病机制，并显示检查点分子（PD-L1，PD-1）的细胞表面表达增加，免疫激活标记物血管紧张素转换酶（ACE）的高表达，但是减少了MHV-1受体CD66a在肺免疫细胞上的检测，肝脏,还有脾脏.除了在所有测定的免疫细胞上减少PD-L1的检测，PD-L1阻断与PD-1和ACE的细胞表面表达增加有关，CD66a的细胞表面检测减少，尽管血糖水平降低，组织缺氧迹象增加，但氧饱和度改善。在肺部，PD-L1mAb促进S100A9，但抑制ACE2的产生同时pAKT激活和降低FOXO1水平。PD-L1mAb促进干扰素-γ，但抑制IL-5和粒细胞-巨噬细胞集落刺激因子（GM-CSF）的产生，有助于降低支气管肺泡灌洗水平的嗜酸性粒细胞和嗜中性粒细胞。在肝脏中，PD-L1mAb增加与巨噬细胞和淋巴细胞募集和肝损伤相关的病毒清除率。PD-L1mAb增加了病毒诱导的损伤介质的产生，血管生成,和可能在COVID-19和ICI相关神经毒性中起作用的神经元活性。PD-L1mAb不影响该鼠模型中的存活。
■在研究1和研究2中，ACE被MHV-1或PD-L1mAb上调，CD66a和ACE2被下调。CD66a不仅是MHV-1受体，而且是公认的免疫检查点和ACE的负调节因子。CD66a和PD-L1或ACE/ACE2之间的串扰可以提供对ICI治疗的见解。这些网络也可能在响应MHV-1和/或PD-L1mAb的S100A9和神经介质的增加产生中起作用。这需要进一步研究。总的来说,这些发现支持了观察性数据,这些数据表明,在出现COVID-19的患者中,先前的ICI治疗并没有改变生存率.
