GLP-1 Targeting Agents Impair Chemoimmunotherapy Effectiveness in Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Immunology
• Endocrinology

Background:

• Glucagon-like peptide-1 receptor (GLP-1R) activation may influence cancer treatment outcomes.
• A comprehensive assessment of GLP-1R expression across human tumors is lacking.

Purpose of the Study:

• To assess GLP-1R expression in human tumors, focusing on triple-negative breast cancer (TNBC).
• To investigate the impact of GLP-1 exposure on TNBC cells and the tumor microenvironment.
• To evaluate the effect of GLP-1 drugs on neoadjuvant chemotherapy response in TNBC patients.

Main Methods:

• Detection of GLP-1R in various human tumor types, with in-depth analysis in TNBC.
• In vitro treatment of TNBC cells with GLP-1 to assess pathway activation, proliferation, drug resistance, and cytokine secretion.
• Spatial transcriptomics to analyze tumor microenvironment changes.
• Retrospective analysis of pathological complete response (pCR) rates in TNBC patients receiving GLP-1 drugs during neoadjuvant chemotherapy.

Main Results:

• GLP-1R is expressed in both immune and tumor cell compartments in TNBC.
• GLP-1 treatment activated survival pathways, increased proliferation, induced paclitaxel resistance, and reduced cytokine secretion in TNBC cells.
• GLP-1 exposure remodeled the tumor microenvironment, induced mesenchymal transition in malignant cells, and disrupted macrophage inflammation.
• Patients on GLP-1 drugs showed significantly lower pCR rates (30.8%) compared to controls (65%) during neoadjuvant chemotherapy.

Conclusions:

• GLP-1R activation in TNBC impacts tumor cell behavior and the tumor microenvironment.
• GLP-1 exposure negatively affects chemoimmunotherapy efficacy in TNBC by impairing treatment responses.
• These findings suggest a potential clinical implication for patients with TNBC undergoing chemotherapy while using GLP-1-based therapies.