Anti-PD-L1 peptide improves survival in sepsis

Abstract

Background Sepsis remains a leading cause of death in most ICUs. Many deaths in sepsis are due to nosocomial infections in patients who have entered the immunosuppressive phase of the disorder. One cause of immunosuppression in sepsis is T-cell exhaustion mediated by programmed cell death-1 (PD-1) interaction with its ligand (PD-L1). Studies demonstrated that blocking the interaction of PD-1 with PD-L1 with knockout mice or inhibitory antibodies reversed T cell dysfunction and improved sepsis survival. This study assessed the efficacy of a novel short-acting peptide (Compound 8) that inhibits PD-1/PD-L1 signaling in a clinically-relevant second-hit fungal sepsis model. Methods Mice underwent cecal ligation and puncture to induce peritonitis. Three days later, mice received intravenous injection of Candida albicans. Forty-eight hours following Candida infection, mice were treated with Compound 8 or inactive peptide. The effect of Candida infection on expression of co-inhibitory molecules, PD-1 and PD-L1 were quantitated by flow cytometry on CD4+, CD8+, natural killer (NK) cells, and NKT cells. The effect of Compound 8 on survival was also examined. Results Four days after fungal infection, PD-1 and/or PD-L1 expressions were markedly increased on CD4+, NK, and NKT cells in septic versus sham-operated mice (%PD-1 on CD4+, 11.9% vs 2.8%; and %PD-L1 on NKT, 14.8% vs 0.5%). Compared to control, Compound 8 caused a two-fold increase in survival from 30% to 60%, p < 0.05. Conclusions Compound 8 significantly improved survival in a clinically-relevant immunosuppressive model of sepsis. These results support immuno-adjuvant therapy targeting T-cell exhaustion in this lethal disease.

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

“…i NKT-cells are themselves regulated by co-inhibitory/checkpoint proteins, most notably PD-1. Initial activation of i NKT-cells is associated with increased PD-1 expression upon i NKT-cells (77) (Figure 4, Component [2]). Young et al (76) showed that direct ligation of PD-1 with its ligand PD-L1 is essential to trafficking and migration of i NKT-cells and PD-1 is essential to regulation of chemokine receptor expression upon i NKT-cells.…”

“…75,76 iNKT cells are themselves regulated by coinhibitory/checkpoint proteins, most notably PD-1. Initial activation of iNKT cells is associated with increased PD-1 expression upon iNKT cells 77 (Fig. 4, Component [2]).…”

Crosstalk between Dendritic Cells and Immune Modulatory Agents against Sepsis

“…Programmed death-1 (PD-1), a co-inhibitory receptor with similarities to BTLA and T-lymphocyte antigen (CTLA)-4, exerts an inhibitory function by regulating the balance among T cell activation, tolerance, and immunopathology, which is often connected with the phenomenon of "T cell exhaustion" [91,92]. Blockade of PD-1 or its ligand PD-L1 hold great potential in reversing immunosuppression in sepsis via arresting lymphocyte apoptosis and preventing monocyte dysfunction [93,94]. Moreover, blockade of PD1-PDL1 or deficiency can significantly elevated the survival rate and reduced the mortality rate in animal models with sepsis caused by C. albicans [95].…”

Undo the brake of tumour immune tolerance with antibodies, peptide mimetics and small molecule compounds targeting PD‐1/PD‐L1 checkpoint at different locations for acceleration of cytotoxic immunity to cancer cells

“…Whereas cellular inhibition of T‐cell tumour immunity involves Treg activity, co‐inhibitory checkpoints are mediated by PD‐1 on the T‐cell with PD‐L1 on tumour cell, and immunosuppression under various conditions such as transformation of neoplastic cells and nosocomial infection. Blocking the interaction of PD‐1 with PD‐L1 by gene knockout or inhibitory antibodies reverses T‐cell dysfunction and improves survival from late‐stage cancer or sepsis . Some other well‐studied checkpoint molecules are CTLA‐4, LAG3, TIM3 (Figure ).…”

“…Blocking the interaction of PD-1 with PD-L1 by gene knockout or inhibitory antibodies reverses T-cell dysfunction and improves survival from late-stage cancer or sepsis. 19 Some other well-studied checkpoint molecules are CTLA-4, LAG3, TIM3 20 ( Figure 1). These molecules, once activated, induce T-cell incompetency or apoptosis by regulating T-cell signalling pathways.…”