Immune Checkpoints in Sepsis and the Path Toward Precision Immunotherapy

Area of Science:

• Immunology
• Critical Care Medicine
• Translational Research

Background:

• Sepsis is a major global cause of death, driven by immune dysfunction.
• Immunosuppression in sepsis leads to mortality and secondary infections.
• Immune checkpoint molecules are key regulators of sepsis-induced immune dysfunction.

Purpose of the Study:

• To review literature on immune checkpoint pathways in sepsis.
• To analyze checkpoint roles, expression, and convergence with reprogramming.
• To evaluate myeloid checkpoints in innate immune dysfunction.

Main Methods:

• Literature review of inhibitory checkpoint pathways (PD-1/PD-L1, CTLA-4, TIM-3, LAG-3, TIGIT, BTLA).
• Analysis of cell-type-specific expression and context-dependent roles.
• Evaluation of myeloid checkpoints (CD47-SIRPα, MerTK).

Main Results:

• Checkpoint molecules have context-dependent protective and pathological roles.
• Monocyte HLA-DR and ferritin identified as biomarkers for patient phenotyping.
• The ImmunoSep trial demonstrated improved outcomes with phenotype-guided immunotherapy.

Conclusions:

• Precision medicine frameworks are essential for checkpoint-based immunotherapies.
• Biomarker-guided stratification is crucial for combination immunotherapies.