CAA-derived IL-6 induced M2 macrophage polarization by activating STAT3

Area of Science:

• Oncology
• Immunology
• Cell Biology

Background:

• Tumor-associated macrophages (TAMs) are key immune cells in breast cancer (BC), often promoting tumor progression.
• TAMs typically display an M2 phenotype, contributing to an immunosuppressive tumor microenvironment (TME).
• Cancer-associated adipocytes (CAAs) are increasingly recognized for their role in BC progression.

Purpose of the Study:

• To investigate the role of IL-6 secreted by CAAs in modulating macrophage polarization.
• To determine the impact of CAA-derived IL-6 on breast cancer progression and metastasis.
• To explore the effect of CAAs on programmed cell death protein ligand 1 (PD-L1) expression in macrophages.

Main Methods:

• Analysis of human BC samples and co-cultures of adipocytes with 4T1 BC cells.
• In vivo studies using mouse tumor-bearing and pulmonary metastasis models.
• Functional assays, qRT-PCR, western blotting, and ELISA to assess macrophage polarization and PD-L1 expression.

Main Results:

• CAAs, found at the invasive front, exhibited a de-differentiated fibroblast phenotype and promoted BC cell malignant behaviors in vitro and in vivo.
• CAAs enhanced M2 macrophage infiltration and activation in the TME, with CAA-educated macrophages further promoting BC cell malignancy.
• CAAs secreted IL-6, inducing M2 macrophage polarization via STAT3 activation and upregulating macrophage PD-L1 expression.

Conclusions:

• CAAs and CAA-educated macrophages significantly enhance breast cancer malignant behaviors.
• CAA-derived IL-6 is a key mediator, driving macrophage migration, M2 polarization (via STAT3), and PD-L1 expression, ultimately promoting BC progression.