AUTHOR=Curran Colleen S. , Cui Xizhong , Li Yan , Jeakle Mark , Sun Junfeng , Demirkale Cumhur Y. , Minkove Samuel , Hoffmann Victoria , Dhamapurkar Rhea , Chumbris Symya , Bolyard Cameron , Iheanacho Akunna , Eichacker Peter Q. , Torabi-Parizi Parizad 

TITLE=Anti-PD-L1 therapy altered inflammation but not survival in a lethal murine hepatitis virus-1 pneumonia model

JOURNAL=Frontiers in Immunology

VOLUME=Volume 14 - 2023

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1308358

DOI=10.3389/fimmu.2023.1308358

ISSN=1664-3224

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 pneumonia model in the absence (Study-1) or presence of prior programmed cell death ligand-1 (PD-L1) antibody (PD-L1mAb) treatment (Study-2). Study-1 examined physiological, thrombotic, and pro-inflammatory responses 2, 5 and 10 days after infection. 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 Study-2, the effects of PD-L1mAb were evaluated 2 and 5 days after infection, identifying reduced PD-L1 detection on immune cells in the lung, liver, and spleen. 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.