Metabolic control of CD47 expression through LAT2-mediated amino acid uptake promotes tumor immune evasion

Abstract

Chemotherapy elicits tumor immune evasion with poorly characterized mechanisms. Here, we demonstrate that chemotherapy markedly enhances the expression levels of CD47 in osteosarcoma tissues, which are positively associated with patient mortality. We reveal that macrophages in response to chemotherapy secrete interleukin-18, which in turn upregulates expression of L-amino acid transporter 2 (LAT2) in tumor cells for substantially enhanced uptakes of leucine and glutamine, two potent stimulators of mTORC1. The increased levels of leucine and enhanced glutaminolysis activate mTORC1 and subsequent c-Myc-mediated transcription of CD47. Depletion of LAT2 or treatment of tumor cells with a LAT inhibitor downregulates CD47 with enhanced macrophage infiltration and phagocytosis of tumor cells, and sensitizes osteosarcoma to doxorubicin treatment in mice. These findings unveil a mutual regulation between macrophage and tumor cells that plays a critical role in tumor immune evasion and underscore the potential to intervene with the LAT2-mediated amino acid uptake for improving cancer therapies.

Echinacea purpurea-derived homogeneous polysaccharide exerts anti-tumor efficacy via facilitating M1 macrophage polarization

“…Considering macrophages are the most abundant immune cell type in TME, 18 , 19 we primarily compared the differently expressed genes (DEGs) in macrophages from the model versus EPPA-treated mice ( Figure 3 D). Transcription of genes involved in innate immune response, cellular response to interferon-gamma/lipopolysaccharide, and immune system process were observed according to the Gene Ontology (GO) enrichment analysis ( Figure 3 E).…”

Immunological and Prognostic Role of Cell Differentiation Trajectory Defined Gene Signature in Glioma

“…The expression of macrophage-related immune checkpoints among trajectories was consistent with the immune/stromal scores and the distribution of macrophages among molecular subtypes. These particular immune checkpoints included the iconic M2 receptors CD206 and CD163 [50][51][52][53] ; CD47-SIRPα, which were functioning as ligand-receptor pairs that transmit phagocytosis signals of macrophages 54,55 ; LILBRs family members of LILRB1, ILLRB2, and LILRB4, who directly expressed on the surface of tumor cells and stimulated tumor cells growth by combining with MHC-56,57 .…”

Intracellular Magnetic Hyperthermia Enables Concurrent Down-Regulation of CD47 and SIRPα To Potentiate Antitumor Immunity

“…Specifically, we observed a reduction in CD47 protein expression in the group treated with FVIO-si CD47 (Supporting Information Figure S11). While M1 phenotype macrophages, known for their tumoricidal activity due to enhanced phagocytosis, , showed limited phagocytosis with SIRPα inhibition (only 31.2%), FVIO-si CD47 treatment (which suppresses the “do not eat me” signal) enhanced phagocytosis to 45.4% ( P < 0.001). Remarkably, FVIO-mediated magnetic hyperthermia treatment, which up-regulates the “eat me” signal and suppresses the “do not eat me” signal, further boosted phagocytosis to 61.1%, a 1.3-fold increase compared to FVIO-si CD47 alone (Figure D,E).…”