Ligand Discrimination in Immune Cells: Signal Processing Insights into Immune Dysfunction in ER+ Breast Cancer

Area of Science:

• Immunology
• Systems Biology
• Signal Transduction

Background:

• Approximately 40% of estrogen receptor-positive (ER+) breast cancer (BC) patients exhibit immune signaling defects at diagnosis.
• These immune defects are linked to poorer overall survival in ER+ breast cancer patients.
• Quantitative characterization of immune signaling errors is crucial for understanding patient prognosis and treatment response.

Purpose of the Study:

• To develop and apply a novel model combining communication theory and signal processing to quantitatively assess ligand discrimination in immune cells.
• To measure immune cell signaling specificity and molecular noise in ER+ breast cancer patients compared to healthy controls.
• To evaluate the impact of JAK1/2 inhibition on immune cell ligand discrimination.

Main Methods:

• A novel model based on communication theory and signal processing was developed to estimate the probability of error in ligand identification.
• High-dimensional spectral flow cytometry was used to measure transcription factors (phosphorylated STATs and SMADs) in immune cells.
• Immune cells from 19 ER+ breast cancer patients and 32 healthy controls were stimulated with various cytokines; additional analysis included 10 healthy donors treated with a JAK1/2 inhibitor.

Main Results:

• Breast cancer patients demonstrated significantly reduced ligand identification accuracy and elevated molecular noise compared to healthy controls.
• Inhibition of JAK1/2 in healthy donors resulted in ligand misidentification and molecular noise rates comparable to or exceeding those in breast cancer patients.
• These findings suggest potential immune cell dysfunction in ER+ breast cancer patients.

Conclusions:

• Immune cell ligand discrimination is impaired in ER+ breast cancer patients, characterized by reduced accuracy and increased molecular noise.
• JAK1/2 inhibition mimics or exacerbates the immune signaling defects observed in breast cancer patients.
• Assessing immune cell ligand discrimination specificity may help optimize the use of signaling kinase inhibitor therapies in breast cancer treatment.