Enhanced Thermogenesis in Triple-Negative Breast Cancer Is Associated with Pro-Tumor Immune Microenvironment

Area of Science:

• Oncology
• Immunology
• Metabolism

Background:

• Cold stress can influence tumor growth and the immune microenvironment.
• Thermogenesis, the process of heat production, is activated by cold stress.
• Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options.

Purpose of the Study:

• To investigate the association between thermogenesis and cancer biology in TNBC.
• To determine if enhanced thermogenesis correlates with a more aggressive TNBC phenotype and an unfavorable tumor microenvironment (TME).
• To explore potential therapeutic strategies targeting thermogenesis in TNBC.

Main Methods:

• Analysis of 6479 breast cancer patients from multiple cohorts (METABRIC, TCGA, GSE96058, GSE20194, GSE25066).
• Utilized Kyoto Encyclopedia of Genes and Genomes (KEGG) thermogenesis score to categorize tumors.
• Examined gene expression, pathway enrichment, and immune cell infiltration markers.

Main Results:

• High-thermogenesis TNBC showed a trend towards worse survival and enrichment in angiogenesis, adipogenesis, and fatty acid metabolism pathways.
• Low-thermogenesis TNBC was associated with cell proliferation pathways (mitotic spindle, E2F targets, G2M checkpoint, MYC targets) and immune responses (IFN-α, IFN-γ).
• High-thermogenesis TNBC exhibited lower levels of cytotoxic T-cell-attracting chemokines (CCL5, CXCL9, CXCL10, CXCL11) and higher levels of MDSC/Treg-attracting chemokine (CXCL12), with increased M2 macrophages and decreased M1 macrophages and Tregs.

Conclusions:

• High-thermogenesis TNBC is linked to a pro-tumorigenic immune microenvironment.
• Thermogenesis may serve as a biomarker for identifying TNBC patients who could benefit from therapies targeting immunosuppression.
• Understanding the role of thermogenesis in TNBC could lead to novel treatment strategies.