Targeting Immune Cell Checkpoints during Sepsis

Abstract

Immunosuppression is increasingly being recognized as one of the causes of increased morbidity and mortality during sepsis. Both innate and adaptive immune system dysfunction have been shown to cause an impaired ability to eradicate the primary infection and also lead to frequent occurrence of secondary opportunistic infections. Pre-clinical and clinical studies have shown that inhibitory immune checkpoint molecules, including programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), cytotoxic T lymphocyte antigen-4 (CTLA-4), T cell membrane protein-3 (TIM-3), Lymphocyte activation-gene-3 (LAG-3) and 2B4, are upregulated during the course of sepsis. Engagement of these inhibitory molecules on various immune cells has been consistently shown to inhibit innate immune cell functions (e.g., phagocytosis, cytokine production and pathogen clearance) and also lead to impaired T cell competence. In numerous pre-clinical models of sepsis, therapeutic agents aimed at blocking engagement of inhibitory immune checkpoints on immune cells have been shown to improve innate and adaptive immune cell functions, increase host resistance to infection and significantly improve survival. Therefore, immunotherapy with immune cell checkpoint inhibitors holds significant potential for the future of sepsis therapy and merits further investigation.

How Clinical Flow Cytometry Rebooted Sepsis Immunology

“…This observation was confirmed by other groups and was completed by the description of the increased expressions of other co‐inhibitory molecules such as BTLA, Tim3, and LAG3 . Based on these observations and on ex vivo studies showing the efficacy of anti‐PD1 and anti‐PD‐L1 blocking antibodies in improving sepsis‐induced T cell alterations , the first clinical trials evaluating immune checkpoint inhibitors that are currently revolutionizing cancer treatment have been completed in septic patients (NCT02960854, NCT02576457). Results from these clinical trials are strongly awaited.…”

Infectious Considerations for Patients on Immune Checkpoint Inhibitors

“…When these CD8 T cells were incubated overnight in isotype (inactive) control antibody, those of septic patients manifested a 70% increase in apoptosis as compared to those of non-septic patients; CD8 T cells incubated in anti-PD-1 antibody had a highly significant decrease in apoptosis [33]. Several other pre-clinical studies have lent further support to the potential role for ICPI in addressing the immunosuppressive manifestations of sepsis to improve survival, as reviewed elsewhere [34].…”

Integrating molecular pathogenesis and clinical translation in sepsis-induced acute respiratory distress syndrome

“…Interestingly, T helper type 17 cells link the adaptive and innate immune systems, in part through IL-17 production and augmentation of neutrophil responses (89). Similar to cancer, reversal of T cell exhaustion has been proposed as a potential therapeutic approach in sepsis (90), and antibodies to CTLA-4, PD-1, and PD-L1 have shown benefit in murine sepsis models (91,92)…”