Deep learning-aided inter-species-comparison reveals shared and distinct molecular patterns in cynomolgus monkey and...

Area of Science:

• Immunology
• Computational Biology
• Translational Medicine

Background:

• Preclinical drug development relies on animal models for immune system studies.
• Cynomolgus monkeys are valuable models, but cross-species immune response differences are not fully understood.
• Understanding molecular immune responses is crucial for translating findings from animal models to human conditions.

Purpose of the Study:

• To develop and apply a cross-species analysis pipeline for single-cell transcriptomics data.
• To investigate and compare the transcriptomic immune response in cynomolgus monkeys and humans following T cell activation.
• To identify shared and divergent molecular patterns in immune responses between species.

Main Methods:

• Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from monkeys and humans.
• In vitro stimulation with anti-CD3/anti-CD28 antibodies and sample collection at 0, 6, and 24 hours.
• Integration of Variational Autoencoder (VAE)-based deep learning, cell-cell communication analysis, differential gene expression, and pathway enrichment.

Main Results:

• Observed shared molecular patterns, including increased CD4+ T cell proportion and decreased monocyte populations, across species.
• Identified species-specific transcriptional clusters in CD8+ T cells (metabolic reprogramming) and NK cells (inflammatory/antiviral programs).
• Found increased cross-species pathway overlap over time, with stronger CD8+ T cell pathway regulation in monkeys and a more pronounced decline in cell-cell communication ligands in humans.

Conclusions:

• The developed computational framework enables systematic cross-species time series analysis of immune responses.
• Findings advance translational research by highlighting shared and divergent immune mechanisms between monkeys and humans.
• This work contributes to the improved development of immunomodulating therapies by providing a deeper understanding of cross-species immune dynamics.