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Media type:
E-Article
Title:
Immune hyporeactivity to bacteria and multiple TLR-ligands, yet no response to checkpoint inhibition in patients just after meeting Sepsis-3 criteria
Contributor:
Bick, Alexandra;
Buys, Willem;
Engler, Andrea;
Madel, Rabea;
Atia, Mazen;
Faro, Francesca;
Westendorf, Astrid M.;
Limmer, Andreas;
Buer, Jan;
Herbstreit, Frank;
Kirschning, Carsten J.;
Peters, Jürgen
Description:
<jats:sec id="sec001">
<jats:title>Rationale</jats:title>
<jats:p>The immune profile of sepsis patients is incompletely understood and hyperinflammation and hypoinflammation may occur concurrently or sequentially. Immune checkpoint inhibition (ICI) may counter hypoinflammation but effects are uncertain. We tested the reactivity of septic whole blood to bacteria, Toll-like receptor (TLR) ligands and to ICI.</jats:p>
</jats:sec>
<jats:sec id="sec002">
<jats:title>Methods</jats:title>
<jats:p>Whole blood assays of 61 patients’ samples within 24h of meeting sepsis-3 criteria and 12 age and sex-matched healthy volunteers. Measurements included pattern/danger-associated molecular pattern (P/DAMP), cytokine concentrations at baseline and in response to TLR 2, 4, and 7/8 ligands, heat-inactivated <jats:italic>Staphylococcus aureus</jats:italic> or <jats:italic>Escherichia coli</jats:italic>, <jats:italic>E</jats:italic>.<jats:italic>coli</jats:italic> lipopolysaccharide (LPS), concentration of soluble and cellular immune checkpoint molecules, and cytokine concentrations in response to ICI directed against programmed-death receptor 1 (PD1), PD1-ligand 1, or cytotoxic T-lymphocyte antigen 4, both in the absence and presence of LPS.</jats:p>
</jats:sec>
<jats:sec id="sec003">
<jats:title>Main results</jats:title>
<jats:p>In sepsis, concentrations of P/DAMPs and inflammatory cytokines were increased and the latter increased further upon incubation <jats:italic>ex vivo</jats:italic>. However, cytokine responses to TLR 2, 4, and 7/8 ligands, heat-inactivated <jats:italic>S</jats:italic>. <jats:italic>aureus</jats:italic> or <jats:italic>E</jats:italic>. <jats:italic>coli</jats:italic>, and <jats:italic>E</jats:italic>. <jats:italic>coli</jats:italic> LPS were all depressed. Depression of the response to LPS was associated with increased in-hospital mortality. Despite increased PD-1 expression on monocytes and T-cells, and monocyte CTLA-4 expression, however, addition of corresponding checkpoint inhibitors to assays failed to increase inflammatory cytokine concentrations in the absence and presence of LPS.</jats:p>
</jats:sec>
<jats:sec id="sec004">
<jats:title>Conclusion</jats:title>
<jats:p>Patients first meeting Sepsis-3 criteria reveal 1) depressed responses to multiple TLR-ligands, bacteria, and bacterial LPS, despite concomitant inflammation, but 2) no response to immune checkpoint inhibition.</jats:p>
</jats:sec>