Investigation of the Effects of a PD1 Inhibitor in a Murine Model of Pneumonia

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Abstract

Bacterial pneumonia is a leading cause of sepsis and septic shock. The host immune response to bacterial pneumonia and other lung infections is thought to include inflammation that stimulates a compensatory anti-inflammatory response. Immune checkpoint molecules are cell surface compensatory receptors that transduce inhibitory signals in response to ligand binding interactions. One inhibitory checkpoint molecule receptor-ligand pair is programmed cell-death 1 (PD-1) and its ligand PD-L1. PD-1 is primarily found on lymphocytes. PD-L1 is expressed on myeloid cells and endothelial, epithelial, and T-cell subsets. Inhibition of PD-1/PD-L1 interactions can lead to persistent inflammation and therapeutic blockade with checkpoint inhibitors (CPIs) has been highly effective for cancers and chronic infections. It has been speculated that PD-1/PD-L1 inhibitors might improve host microbial defenses in bacterial sepsis. However, while monoclonal antibodies (mAb) directed against PD-1 or PD-L1 improve survival in some animal sepsis models, their effects in two Phase-1b trials involving septic patients have not led to broader clinical investigation. Although pneumonia was the most frequent cause of sepsis in these clinical sepsis trials, in vivo studies have not examined lung immune cell checkpoint molecule expression during acute pulmonary bacterial challenge. Also, in a systematic review we conducted no preclinical study examined the survival effects of CPIs with lung infection. Determining whether and how checkpoint molecule expression changes with differing levels of pulmonary infection and over time is necessary to understand their pathogenic role and usefulness as a therapeutic target during pneumonia. To answer these questions, using an intratracheal (IT) Staphylococcus aureus (SA) mouse pneumonia model, we first investigated whether SA doses, producing low or high lethality rates (LD- and HD-SA respectively), would affect lung immune cell PD-L1 and PD-1 expression over time (Study 1). We hypothesized that HD-SA would induce higher immune cell PD-1 and PD-L1 expression levels than LD-SA since human monocyte PD-L1 increases with increasing doses of SA in vitro. We then tested the survival effect of an anti-PD-L1 monoclonal antibody (PD-L1mAb) in response to LD-SA versus HD-SA pneumonia (Study 2). Here, we hypothesized that PD-L1mAb treatment would enhance immunity during HD-SA infection, resulting in improved survival and bacterial clearance, but might also cause increased inflammatory injury. LD-SA and HD-SA produced lethality of 15% and 70% respectively by 168h. At 24h, LD-infected animals exhibited increased lung monocyte PD-L1 expression (p=0.0002) but lower bacterial counts (p=0.0002) compared to HD-animals. By 48h, either infection induced lung neutrophil and macrophage PD-L1 expression (p<0.0001). Anti-PD-L1 treatment at the time of infection and at 24h infection with low to high doses of SA reduced PD-L1 detection but did not affect survival or bacterial clearance. Anti-PD-L1 therapy did not alter survival in this pneumonia model. Pre-clinical studies of additional common pathogens and septic foci are needed. A manuscript summarizing this work was recently submitted and accepted for publication in the Journal of Infectious Diseases in May 2021. We have also completed a systematic review of the literature surrounding checkpoint molecule expression on circulating immune cells from patients with sepsis compared to critically ill non septic patients or healthy volunteers. This was published in Critical Care Medicine in September 2020. Additionally, we have performed a systematic review with meta-analysis of all studies employing animal models of sepsis and severe infection that have examined the mortality effects of checkpoint blockade. This work was publishes in Intensive Care Medicine Experimental in February 2020.