Suppression of macrophage membrane cholesterol efflux by SLAMF7-induced IL-7 signaling improves immunotherapy efficacy in hepatocellular carcinoma.

Abstract

Background: The limited efficacy of immunotherapy in hepatocellular carcinoma (HCC) is largely attributed to the formation of an immunosuppressive tumor microenvironment, in which abnormal cholesterol metabolism plays an important role. Here, we investigated the effects of signaling lymphocytic activation molecule family member 7 (SLAMF7) on the cholesterol metabolism of HCC.

Methods: Metabolomics was performed in spontaneous HCC tissues with hepatocyte-specific Slamf7 knockout. An in vitro coculture system was constructed, and cytokine matrix, protein profiling, and transcriptome sequencing were applied to explore the function of SLAMF7 in HCC.

Results: Profiling of the metabolomics of spontaneous HCC with Slamf7 knockout and the proteomics of SLAMF7-overexpressing HCC cells clarified the inhibition of cholesterol synthesis by SLAMF7 in HCC cells. Furthermore, HCC cell-intrinsic SLAMF7 inhibited membrane cholesterol efflux and function reprogramming in macrophages. Mechanistically, SLAMF7 interacted with DHCR24 and enhanced the binding and ubiquitination degradation of DHCR24 by MARCH6 via its intracellular domain to inhibit cholesterol synthesis in HCC cells. Reduction of cholesterol content in lipid rafts impaired the AKT activation and promoted entry of dephosphorylated FOXO1 into nucleus for IL-7 transcription. Subsequently, IL-7 reduced membrane cholesterol efflux by inhibiting the NF-κB pathway and ABCA1 transcription in macrophages. Pharmacological enhancement of IL-7 signaling improved the efficacy of anti-PD-1 antibody in HCC mouse models with low SLAMF7 level.

Conclusions: Our study molecularly identifies a key role of SLAMF7 in cholesterol metabolism and trafficking between HCC cells and macrophages and gives a rationale for targeting IL-7 signaling as an effective strategy to sensitize HCC to immunotherapy.