Dysregulated STAT3 Signaling Defines a Targetable, High-Mortality Subphenotype of Pediatric Sepsis

Monday, February 24, 2025

2:30pm – 3:30pm Eastern Time

Location: Connections Central Theater 1

Robert B. Lindell, MD

Childrens Hospital of Philadelphia

Disclosure(s): No relevant financial relationship(s) to disclose.
SS

Samir Sayed, BS

Division of Allergy and Immunology, Department of Pediatrics
Children’s Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania

Disclosure information not submitted.
JC

Jose S. Campos, BA

Division of Allergy and Immunology, Department of Pediatrics
Children’s Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania

Disclosure information not submitted.
MK

Montana Knight, PhD

Department of Biomedical and Health Informatics
Children's Hospital of Philadelphia

Disclosure information not submitted.
AM

Andrea A. Mauracher, MD

Division of Allergy and Immunology, Department of Pediatrics
Children’s Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania

Disclosure information not submitted.
CH

Ceire A. Hay, BS

Division of Allergy and Immunology, Department of Pediatrics
Children’s Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania

Disclosure information not submitted.
JF

Julie C. Fitzgerald, MD, PhD, MSCE

Division of Critical Care Medicine, Department of Anesthesia and Critical Care
Children’s Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania

Disclosure information not submitted.
NY

Nadir Yehya, MD, MSCE

Children's Hospital of Philadelphia

Disclosure(s): No relevant financial relationship(s) to disclose.
EB

Edward M. Behrens, MD

Division of Rheumatology, Department of Pediatrics
Children’s Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania

Disclosure information not submitted.
AF

Alexandra F. Freeman, MD

Laboratory of Clinical Immunology and Microbiology
National Institute of Allergy and Infectious Diseases, National Institutes of Health

Disclosure information not submitted.
JB

Jenna R. E. Bergerson, MD, MPH

Laboratory of Clinical Immunology and Microbiology
National Institute of Allergy and Infectious Diseases, National Institutes of Health

Disclosure information not submitted.
SH

Steven M. Holland, MD

Laboratory of Clinical Immunology and Microbiology
National Institute of Allergy and Infectious Diseases, National Institutes of Health

Disclosure information not submitted.
JL

Jennifer W. Leiding, MD

Division of Allergy and Immunology, Department of Pediatrics
Johns Hopkins University

Disclosure information not submitted.
Scott L. Weiss, MD, FCCM

Nemours Childrens Hospital
Sidney Kimmel Medical Center at Thomas Jefferson University

Disclosure information not submitted.
MH

Mark W. Hall, MD

Division of Critical Care, Department of Pediatrics
Nationwide Children's Hospital

Disclosure information not submitted.
DT

Deanne M. Taylor, PhD

Department of Biomedical and Health Informatics
Children’s Hospital of Philadelphia

Disclosure information not submitted.
RF

Rui Feng, PhD

Department of Biostatistics, Center for Clinical Epidemiology, Biostatistics, and Informatics
University of Pennsylvania

Disclosure information not submitted.
EW

E. John Wherry, PhD

Department of Systems Pharmacology and Translational Therapeutics
Perelman School of Medicine, University of Pennsylvania

Disclosure information not submitted.
Nuala J. Meyer, MD, MS

Professor
University of Pennsylvania Perelman School of Medicine

Disclosure information not submitted.
SH

Sarah E. Henrickson, MD, PhD

Division of Allergy and Immunology, Department of Pediatrics
Children’s Hospital of Philadelphia and the Perelman School of Medicine, University of Pennsylvania

Disclosure information not submitted.

Disclosure(s):

Robert B. Lindell, MD: No relevant financial relationship(s) to disclose.

Nadir Yehya, MD, MSCE: No relevant financial relationship(s) to disclose.

Introduction: Sepsis is the leading cause of death of hospitalized children worldwide. Despite the link between immune dysregulation and mortality in sepsis, it remains unclear which host immune factors contribute causally to adverse sepsis outcomes. We hypothesized that plasma subphenotypes would predict organ dysfunction and targetable mechanisms of immune dysregulation.

Methods: We enrolled a prospective cohort of 88 children with multiple organ dysfunction syndrome (MODS), including patients with and without sepsis, to define molecular subphenotypes. We collected PBMC and plasma samples at MODS onset. We performed multi-omic immune profiling with plasma proteomics (Olink, n=1536 proteins) and then flow cytometry. We used consensus clustering to identify prognostic subphenotypes; gene set variation analysis (GSVA) to measure expression of proinflammatory pathways by subphenotype; and single-cell RNA-sequencing (scRNA-seq) to identify the impact of STAT3 hyperactivation on T cell immunometabolic state. Finally, we compared our MODS subphenotypes to patients with inborn errors of immunity (IEI).

Results: Using consensus clustering of plasma proteins, we defined three subphenotypes (Group A, B, C) at MODS onset. Group C patients have increased cumulative organ dysfunction scores (p < 0.001) and mortality (p=0.03) compared to Groups A/B. By flow cytometry, the abundance of effector and memory CD8+ T cells were markedly reduced in Group C patients (all p< 0.001) compared to Group A/B. Using GSVA, we identified that Group C patients had increased IL-6/JAK/STAT3 (p < 0.001), IL-2/JAK/STAT5 (p < 0.001), and TNF/NFkB signaling (p < 0.05), and reduced PI3K/AKT/MTOR signaling (p < 0.001) in comparison to Group A. By scRNA-seq, we noted that CD4+, CD8+, and TCRγδ+ T cells from Group C patients had increased IL-6/JAK/STAT3 signaling (all p< 0.001) and low glycolysis and oxidative phosphorylation activity (p < 0.01) at the single-cell level. In our IEI analysis, both Group C patients and STAT3 gain-of-function patients had elevated IL-6/JAK/STAT3 signaling compared to Group A (p < 0.001).

Conclusions: Three prognostic molecular sepsis subphenotypes can be defined at MODS onset using proteomics. Within the highest severity subphenotype, we have identified a pathologic and potentially targetable role for STAT3 hyperactivation.