The prognostic impact of SIGLEC5-induced impairment of CD8+ T cell activation in sepsis

Abstract

Immune checkpoint; Sepsis; T-cell exhaustion

Punto de control inmunológico; Septicemia; Agotamiento de células T

Punt de control immunitari; Sèpsia; Esgotament de cèl·lules T

Background Sepsis is associated with T-cell exhaustion, which significantly reduces patient outcomes. Therefore, targeting of immune checkpoints (ICs) is deemed necessary for effective sepsis management. Here, we evaluated the role of SIGLEC5 as an IC ligand and explored its potential as a biomarker for sepsis. Methods In vitro and in vivo assays were conducted to both analyse SIGLEC5's role as an IC ligand, as well as assess its impact on survival in sepsis. A multicentre prospective cohort study was conducted to evaluate the plasmatic soluble SIGLEC5 (sSIGLEC5) as a mortality predictor in the first 60 days after admission in sepsis patients. Recruitment included sepsis patients (n = 346), controls with systemic inflammatory response syndrome (n = 80), aneurism (n = 11), stroke (n = 16), and healthy volunteers (HVs, n = 100). Findings SIGLEC5 expression on monocytes was increased by HIF1α and was higher in septic patients than in healthy volunteers after ex vivo LPS challenge. Furthermore, SIGLEC5-PSGL1 interaction inhibited CD8+ T-cell proliferation. Administration of sSIGLEC5r (0.8 mg/kg) had adverse effects in mouse endotoxemia models. Additionally, plasma sSIGLEC5 levels of septic patients were higher than HVs and ROC analysis revealed it as a mortality marker with an AUC of 0.713 (95% CI, 0.656–0.769; p < 0.0001). Kaplan–Meier survival curve showed a significant decrease in survival above the calculated cut-off (HR of 3.418, 95% CI, 2.380–4.907, p < 0.0001 by log-rank test) estimated by Youden Index (523.6 ng/mL). Interpretation SIGLEC5 displays the hallmarks of an IC ligand, and plasma levels of sSIGLEC5 have been linked with increased mortality in septic patients.

This work was supported by grants from Instituto de Salud Carlos III (ISCIII) and “Fondos FEDER” to ELC (PIE15/00065, PI18/00148, PI14/01234, PI21/00869), to PP (20859/PI/18) and to CdF (PI21/01178), and received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowaska-Curie grant agreement to KMH (No. 713673; “laCaixa”). R.L.-R. was supported by “Predoctotales de formación en Investigación” (PFIS) grant FI19/00334 and J.A.-O. by Sara Borrell grant CD21/00059 from ISCIII. The Vall d'Hebron University Hospital and Vall d’Hebron Research Institute were supported by Plan Nacional de I+D+i 2013–2016, the ISCIII and Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0003)—co-financed by European Development Regional Fund “A way to achieve Europe”, and by the European Union’s Horizon 2020 Research and Innovation Program (JCRR, RF, JJGL, AF). Authors thank Emilio Llanos for his technical assistance.