Circulating Immune Bioenergetic, Metabolic, and Genetic Signatures Predict Melanoma Patients' Response to Anti-PD-1...

Area of Science:

• Immunology
• Metabolomics
• Cancer Research

Background:

• Immunotherapy with checkpoint inhibitors offers improved outcomes for various cancers, but patient response rates vary.
• Predictive biomarkers are essential for guiding treatment decisions and overcoming therapeutic resistance.

Purpose of the Study:

• To compare the bioenergetics of immune cells and plasma metabolomic profiles in melanoma patients undergoing anti-PD-1 therapy.
• To correlate transcriptional and metabolic changes in peripheral blood mononuclear cells (PBMCs) and plasma with treatment response.

Main Methods:

• Collected baseline plasma and PBMCs from melanoma patients treated with anti-PD-1 therapy.
• Performed bioenergetic assays, metabolomic profiling, and single-cell RNA sequencing (scRNAseq).
• Correlated metabolic and transcriptional data with patient response to immunotherapy.

Main Results:

• Responders exhibited higher PBMC reserve respiratory capacity and basal glycolytic activity than non-responders.
• Distinct metabolic signatures were observed between responder and non-responder patient plasma.
• Upregulation of glycolysis-regulating T-cell genes, including SLC2A14 (Glut-14), was identified in responders.
• Elevated cell surface expression of Glut-14 was confirmed in circulating immune cells of responders.

Conclusions:

• A glycolytic metabolic signature characterizes responders to checkpoint inhibitor therapy.
• Extracellular acidification rate (ECAR) and lactate-to-pyruvate ratio correlate with overall survival.
• Blood-based bioenergetics and metabolomics show promise as predictive biomarkers for immunotherapy response.