The Neonatal Innate Immune Response to Sepsis: Checkpoint Proteins as Novel Mediators of This Response and as Possible Therapeutic/Diagnostic Levers

Abstract

Sepsis, a dysfunctional immune response to infection leading to life-threatening organ injury, represents a significant global health issue. Neonatal sepsis is disproportionately prevalent and has a cost burden of 2-3 times that of adult patients. Despite this, no widely accepted definition for neonatal sepsis or recommendations for management exist and those created for pediatric patients are significantly limited in their applicability to this unique population. This is in part due to neonates' reliance on an innate immune response (which is developmentally more prominent in the neonate than the immature adaptive immune response) carried out by dysfunctional immune cells, including neutrophils, antigen-presenting cells such as macrophages/monocytes, dendritic cells, etc., natural killer cells, and innate lymphoid regulatory cell sub-sets like iNKT cells, γδ T-cells, etc. Immune checkpoint inhibitors are a family of proteins with primarily suppressive/inhibitory effects on immune and tumor cells and allow for the maintenance of self-tolerance. During sepsis, these proteins are often upregulated and are thought to contribute to the long-term immunosuppression seen in adult patients. Several drugs targeting checkpoint inhibitors, including PD-1 and PD-L1, have been developed and approved for the treatment of various cancers, but no such therapeutics have been approved for the management of sepsis. In this review, we will comparatively discuss the role of several checkpoint inhibitor proteins, including PD-1, PD-L1, VISTA, and HVEM, in the immune response to sepsis in both adults and neonates, as well as posit how they may uniquely propagate their actions through the neonatal innate immune response. We will also consider the possibility of leveraging these proteins in the clinical setting as potential therapeutics/diagnostics that might aid in mitigating neonatal septic morbidity/mortality.

Keywords: HVEM; PD-1; PD-L1; VISTA; checkpoint inhibitor; neonate; sepsis.

Figure 1

PD-1 suppresses T-cell activation by inhibiting several kinase pathways. T-cell activation occurs when the TCR binds the antigen (Ag) presented by MHC II. This first signal results in ZAP70, Lck, and Fyn recruitment to the CD3-ζ chain proximal to the TCR. The first signal promotes the ERK/MAPK and PKC-θ activation. The second signal occurs when CD28 binds to B7-1/2 and results in PI3K recruitment and downstream AKT pathway activation. PD-1 intrinsically suppresses T-cell activation. Upon interaction with PD-L1/2 the ITSM domain of PD-1 recruits SHP-1/2. Activated SHP-1/2 inhibit ZAP70 and PKC-θ phosphorylation. The ITIM domain of PD-1 is also phosphorylated and recruits SHP-1. This activated SHP-1 inhibits PI3K phosphorylation resulting in suppression of the AKT pathway. These mechanisms of PD-1 induced suppression results in reduced cytokine production, metabolic activity, proliferation, and B-cell lymphoma-extra large (Bcl-X_L) mediated survival.

Figure 2

Timeline of therapeutic applications of checkpoint inhibitor proteins. This timeline includes the initial FDA approval for each of the approved medications targeting checkpoint inhibitor proteins (PD-1, PD-L1, and CTLA-4), as well as the publications of phase 1 clinical trial results for two of these medications in septic patients.