Frontline Science: Defects in immune function in patients with sepsis are associated with PD-1 or PD-L1 expression and can be restored by antibodies targeting PD-1 or PD-L1

Abstract

Sepsis is a heterogeneous syndrome comprising a highly diverse and dynamic mixture of hyperinflammatory and compensatory anti-inflammatory immune responses. This immune phenotypic diversity highlights the importance of proper patient selection for treatment with the immunomodulatory drugs that are entering clinical trials. To better understand the serial changes in immunity of critically ill patients and to evaluate the potential efficacy of blocking key inhibitory pathways in sepsis, we undertook a broad phenotypic and functional analysis of innate and acquired immunity in the same aliquot of blood from septic, critically ill nonseptic, and healthy donors. We also tested the ability of blocking the checkpoint inhibitors programmed death receptor-1 (PD-1) and its ligand (PD-L1) to restore the function of innate and acquired immune cells. Neutrophil and monocyte function (phagocytosis, CD163, cytokine expression) were progressively diminished as sepsis persisted. An increasing frequency in PD-L1-suppressor phenotype neutrophils [low-density neutrophils (LDNs)] was also noted. PD-L1 LDNs and defective neutrophil function correlated with disease severity, consistent with the potential importance of suppressive neutrophil populations in sepsis. Reduced neutrophil and monocyte function correlated both with their own PD-L1 expression and with PD-1 expression on CD8 T cells and NK cells. Conversely, reduced CD8 T cell and NK cell functions (IFN-γ production, granzyme B, and CD107a expression) correlated with elevated PD-L1 LDNs. Importantly, addition of antibodies against PD-1 or PD-L1 restored function in neutrophil, monocyte, T cells, and NK cells, underlining the impact of the PD-1:PD-L1 axis in sepsis-immune suppression and the ability to treat multiple deficits with a single immunomodulatory agent.

Neutrophils as myeloid‐derived suppressor cells

“…In fact, patients with gastric cancer have a high infiltration of neutrophils in tumours, which show an activated CD54+ phenotype, a high expression of PD‐L1 and were found to suppress normal T‐cell immunity in vitro . These PD‐L1+ neutrophils are also described in sepsis patients . The presence of PD‐L1+ neutrophils is associated with disease progression and the overall survival of gastric cancer or sepsis patients, where the immune suppression could be reversed by blocking PD‐L1 on the activated neutrophils, indicating that the recently developed therapeutics against PD‐1 and PD‐L1 have the potential to neutralize the suppressive activity of MDSCs.…”

“…No extra stimulus sepsis patients. 61 The presence of PD-L1+ neutrophils is associated with disease progression and the overall survival of gastric cancer or sepsis patients, where the immune suppression could be reversed by blocking PD-L1 on the activated neutrophils, 60,61 indicating that the recently developed therapeutics against PD-1 and PD-L1 have the potential to neutralize the suppressive activity of MDSCs.…”

Sepsis erodes CD8+ memory T cell-protective immunity against an EBV homolog in a 2B4-dependent manner

“…Thus, our data suggest that blocking the 2B4 signaling pathway may hold promise as a therapeutic target to modulate the immune system and maintain protective immunity in the setting of sepsis. There is precedent for this as therapeutic blockade of PD‐1 and PD‐L1 has been tested in clinical trials to improve immune dysregulation following sepsis . Indeed, we recently showed that pharmacologic blockade of 2B4 reduced sepsis‐induced mortality in a model of CLP .…”

A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis

“…Work by Young et al (51), using a cecal slurry model, documented that PD-1 gene deficiency also confers a survival advantage in this model of polymicrobial sepsis in neonatal mice. Several studies have also shown a clear role for PD-1 in modulating the geriatric immune response to sepsis (53, 54). …”