The fatty acid receptor CD36 promotes macrophage infiltration via p110γ signaling to stimulate metastasis

Abstract

IntroductionMetabolic 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. ObjectiveThis study aims to elucidate the role of the fatty acid translocase CD36 in the regulation of TAM accumulation. MethodsThe 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. ResultsWe 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. ConclusionCD36 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.