Multiscale modeling reveals synergy between CCL19 and PD-1 blockade in reshaping the TNBC microenvironment

Area of Science:

• Oncology
• Immunotherapy
• Computational Biology

Background:

• Triple-negative breast cancer (TNBC) poses significant clinical challenges due to its immunosuppressive microenvironment and limited treatment options.
• Combination therapy involving immune checkpoint blockade and CCL19 has emerged as a promising strategy for TNBC.
• Understanding the synergistic mechanisms between CCL19 and anti-PD-1 therapy is crucial for optimizing treatment outcomes.

Purpose of the Study:

• To systematically investigate the synergistic mechanisms between CCL19 and anti-PD-1 therapy in TNBC.
• To develop a mathematical model integrating cellular and molecular scales for predicting tumor evolution under therapy.
• To identify novel biomarkers and optimal therapeutic strategies for TNBC.

Main Methods:

• Development of a multiscale mathematical model to simulate tumor-immune interactions in TNBC.
• Integration of cellular and molecular dynamics to capture complex therapeutic responses.
• Proposal and validation of quantitative indicators: TRVI, TEDI, and IHTRI.

Main Results:

• The mathematical model confirmed the immunostimulatory synergy between CCL19 and anti-PD-1 therapy in TNBC.
• Immune heterogeneity significantly modulates the synergistic efficacy of combination therapy.
• A novel dynamic biomarker, (CTLs × CCL19)/PD-L1, demonstrated significant predictive (AUC=0.86) and prognostic value (p=0.019).

Conclusions:

• The study provides a theoretical framework for understanding CCL19-mediated immunostimulation combined with anti-PD-1 therapy in TNBC.
• Virtual clinical trials suggest that administering anti-PD-1 therapy before CCL19 injection yields greater clinical benefits.
• The identified biomarker offers potential for personalized treatment strategies in TNBC.