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Macrophages in Tumor-Associated Adipose Microenvironment Accelerate Tumor Progression

Bei Li1, Siqing Liu2, Qian Yang2

  • 1Department of Pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, P. R. China.

Advanced Biology
|October 21, 2022
PubMed

Insights

Tumor cells and adipocytes promote immunosuppressive macrophages via exosomal miRNA-155, driving tumor growth. Inhibiting this pathway retards breast cancer progression.

Area of Science:

  • Oncology
  • Immunology
  • Cell Biology

Background:

  • Adipose-tissue macrophages (ATMs) are key components of the tumor-adipose microenvironment (TAME).
  • Tumor-adipocyte interactions influence macrophage plasticity and function, but mechanisms remain unclear.
  • Identifying these mechanisms is crucial for understanding and targeting cancer progression.

Purpose of the Study:

  • To elucidate the mechanisms by which tumor-adipocyte crosstalk regulates macrophage behavior in the TAME.
  • To investigate the role of exosomal microRNA-155 (miRNA-155) in mediating this crosstalk.
  • To evaluate the therapeutic potential of targeting this pathway in preclinical cancer models.

Main Methods:

  • Single-cell RNA-sequencing of macrophages in the TAME.
  • Co-culture systems of tumor cells and adipocytes.
  • Analysis of exosomal miRNA levels and their downstream effects on adipocyte and macrophage function.
  • In vivo studies involving genetic manipulation (macrophage deletion, miRNA inhibition) and pharmacological inhibition (chemokines, STAT3 phosphorylation).

Main Results:

  • A subset of immunosuppressive CD163+ macrophages expressing CCL2 and CCL5 were identified in the TAME, surrounding adipocytes.
  • Exosomal miRNA-155 levels were elevated in tumor-adipocyte co-cultures, promoting CCL2 and CCL5 release from adipocytes via the SOCS6/STAT3 pathway.
  • Inhibition of exosomal miRNA-155 reduced CCL2/CCL5 levels and tumor growth.
  • Macrophage deletion, chemokine inhibition, or STAT3 suppression decreased adipocyte-induced tumor proliferation.

Conclusions:

  • Exosomal miRNA-155 secreted by tumor cells in the TAME drives adipocyte-mediated immunosuppression and macrophage polarization.
  • This miRNA-155/adipocyte/macrophage axis represents a critical mechanism for tumor progression.
  • Targeting exosomal miRNA-155 or downstream signaling pathways holds therapeutic promise for cancers associated with the TAME.
Keywords:
adipocytescancerexosomesmacrophagesobesity

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