Alternations in inflammatory macrophage niche drive phenotypic and functional plasticity of Kupffer cells

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Inflammatory signals recruit monocytes, differentiating into pro-inflammatory macrophages.
• The role of inflammatory monocytes in disease progression and their potential as therapeutic targets are under investigation.

Purpose of the Study:

• To investigate the origin and replenishment mechanisms of liver metastasis-associated macrophages (LMAMs).
• To evaluate the potential of targeting monocyte recruitment and macrophage proliferation for cancer immunotherapy.

Main Methods:

• Utilized multiple lineage-tracing models.
• Employed a proliferation-recording system and Kupffer cell (KC)-tracing in a monocyte-deficient background.
• Investigated epigenetic reprogramming of KCs.

Main Results:

• Monocyte-derived macrophages (mo-macs) are the primary source of immunosuppressive LMAMs.
• Genetic ablation of mo-macs only marginally reduced LMAMs.
• LMAMs were replenished by local macrophage proliferation or Kupffer cell infiltration and reprogramming.

Conclusions:

• Liver metastasis-associated macrophages are replenished through local proliferation or Kupffer cell infiltration and reprogramming.
• Simultaneous blockade of monocyte recruitment and macrophage proliferation may effectively target immunosuppressive myelopoiesis.
• Reprogramming the tumor microenvironment towards an immunostimulatory state is a promising therapeutic strategy.