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Updated: Jun 10, 2025
Isolation Protocol of Mouse Monocyte-derived Dendritic Cells and Their Subsequent In Vitro Activation with Tumor Immune Complexes
Published on: May 31, 2018
The fatty acid receptor CD36 promotes macrophage infiltration via p110γ signaling to stimulate metastasis
Hong Qin1, Anhua Xiao2, Qiannan Lu2
1Centre for Lipid Research & Chongqing Key Laboratory of Metabolism on Lipid and Glucose, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, Chongqing 400016, China; Department of Cancer Center, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China.
Introduction:
Metabolic regulators are key in controlling immune cell fate in the tumor microenvironment. The accumulation of tumor-associated macrophages (TAMs) in cancer greatly contributes to metastasis and poor outcome. However, the metabolic pathways responsible for TAM accumulation are largely unknown.
Objective:
This study aims to elucidate the role of the fatty acid translocase CD36 in the regulation of TAM accumulation.
Methods:
The immune profile was analyzed in patients with liver metastasis by CIBERSORT. Immunohistostaining of CD68 and CD36 was conducted in clinical specimens from patients with liver metastasis. Myeloid-specific CD36 knockout mice and their littermates were used to establish preclinical liver metastasis models. Subsequently, a series of experiments were used to explore the underlying mechanisms of how CD36 regulates TAM population.
Results:
We found that massive TAM accumulation in patients with liver metastasis is associated with an upregulation of CD36 on TAMs. Liver metastasis is abundantly infiltrated by TAMs that are derived from circulating monocytes, but not tissue-resident macrophages. Myeloid-specific CD36 knockout specifically reduced and inactivated monocyte-differentiated macrophages, resulting in diminished immune suppression and attenuated liver metastasis. The protect effects of CD36 knockout can be abrogated by blockade of macrophage recruitment through CCR2 or the p110γ isoform of PI3K downstream of it. Mechanically, CD36 reprogrammed the lipid metabolism of macrophages, in which sphingolipids were significantly downregulated, that contributed to weakened lipid raft-dependent activation of p110γ.
Conclusion:
CD36 expands TAM population by promoting the recruitment of circulating monocytes through CCL2/CCR2/p110γ signaling. Our findings provide evidence for targeting CD36 as a therapeutic strategy against liver metastasis.
Insights
The fatty acid translocase CD36 promotes tumor-associated macrophage (TAM) accumulation in liver metastasis by recruiting monocytes. Targeting CD36 may offer a new therapeutic strategy to combat cancer metastasis.
Area of Science:
- Immunology
- Metabolic pathways
- Cancer biology
Background:
- Immune cell metabolism influences the tumor microenvironment.
- Tumor-associated macrophages (TAMs) drive cancer metastasis and poor outcomes.
- Metabolic pathways driving TAM accumulation remain largely unknown.
Purpose of the Study:
- To investigate the role of fatty acid translocase CD36 in regulating TAM accumulation.
- To elucidate the mechanisms by which CD36 influences TAM populations.
Main Methods:
- Analysis of immune profiles in liver metastasis patients using CIBERSORT.
- Immunohistochemical staining for CD68 and CD36 in clinical specimens.
- Utilizing myeloid-specific CD36 knockout mice to model liver metastasis.
Main Results:
- Increased CD36 expression on TAMs correlates with massive TAM accumulation in liver metastasis.
- TAMs in liver metastasis originate from circulating monocytes.
- CD36 knockout reduced monocyte-derived macrophages, suppressed immune suppression, and attenuated liver metastasis.
- CD36 reprograms macrophage lipid metabolism, downregulating sphingolipids and impairing p110γ activation.
Conclusions:
- CD36 promotes TAM expansion by enhancing circulating monocyte recruitment via CCL2/CCR2/p110γ signaling.
- Targeting CD36 presents a potential therapeutic strategy for liver metastasis.
