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Depleting regulatory T cells (T reg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral T reg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral T reg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-β signaling, programming T reg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in T reg cells suppressed tumor growth accompanied by a decrease in intratumoral T reg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral T reg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME. Tumor environments are highly acidic due to high concentrations of lactic acid. Ho and colleagues report that tumor-infiltrating regulatory T cells adapt to this tumor environment by upregulating expression of CD36, which allows them to use fatty acids to fuel their metabolism.

The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44 bright cells in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36 + metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36 + metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis. Human oral carcinoma cells expressing high levels of the fatty acid receptor CD36 initiate metastasis in mouse models, and metastasis is increased by palmitic acid or a fatty diet and decreased by blockade of CD36. Metastasis-initiating cells in oral carcinoma The ability to identify cells with metastatic potential is of clinical importance for the development of anti-metastatic treatment. Salvador Aznar Benitah and colleagues have identified high metastatic potential in a population of cells expressing high levels of the fatty acid receptor CD36 in human oral carcinoma samples. The cells initiate metastasis in mouse models. Metastasis is increased by palmitic acid or a fatty diet, and decreased by CD36 blockade.

BackgroundCD36, a multi-ligand scavenger receptor, has been associated with several cancers. Many studies have revealed that CD36 contributed to cancer malignancy. This study aimed to reveal the function of CD36 expression in pancreatic ductal adenocarcinoma (PDAC).MethodsCD36 expression was characterized using immunohistochemistry in 95 clinical specimens resected from patients with PDAC. We divided patients into two groups, with different CD36 expression levels, and analyzed and compared their prognoses. CD36 expression was also assessed in PDAC cell lines. Gemcitabine-resistant (GR) PDAC cell lines were transfected with small interfering RNA (siRNA) that specifically targeted CD36 to evaluate chemoresistance and apoptosis.ResultsIn resected PDAC samples, CD36 expression was significantly correlated with microinvasion into the venous system (p = 0.0284). Patients with high CD36 expression had significantly lower overall survival (OS) and recurrence-free survival (RFS) rates than patients with low expression; thus, CD36 was an independent prognostic factor for OS and RFS. In subgroup analyses, CD36 was an independent risk factor for OS and RFS in 59 patients treated with gemcitabine adjuvant chemotherapy. CD36 expression was upregulated in PDAC–GR cell lines compared with the PDAC parent cell line. Transduction with siRNA downregulated CD36, which reduced PDAC cell resistance to gemcitabine and inhibited anti-apoptosis proteins.ConclusionCD36 expression influenced gemcitabine resistance by regulating anti-apoptosis proteins. High CD36 expression was a significant, unfavorable prognostic factor in PDAC. Anti-CD36 treatment might serve as an optional treatment for lowering resistance to gemcitabine.

The impact of lipotoxicity on the development of lung fibrosis is unclear. Saturated fatty acids, such as palmitic acid (PA), activate endoplasmic reticulum (ER) stress, a cellular stress response associated with the development of idiopathic pulmonary fibrosis (IPF). We tested the hypothesis that PA increases susceptibility to lung epithelial cell death and experimental fibrosis by modulating ER stress. Total liquid chromatography and mass spectrometry were used to measure fatty acid content in IPF lungs. Wild-type mice were fed a high-fat diet (HFD) rich in PA or a standard diet and subjected to bleomycin-induced lung injury. Lung fibrosis was determined by hydroxyproline content. Mouse lung epithelial cells were treated with PA. ER stress and cell death were assessed by Western blotting, TUNEL staining, and cell viability assays. IPF lungs had a higher level of PA compared with controls. Bleomycin-exposed mice fed an HFD had significantly increased pulmonary fibrosis associated with increased cell death and ER stress compared with those fed a standard diet. PA increased apoptosis and activation of the unfolded protein response in lung epithelial cells. This was attenuated by genetic deletion and chemical inhibition of CD36, a fatty acid transporter. In conclusion, consumption of an HFD rich in saturated fat increases susceptibility to lung fibrosis and ER stress, and PA mediates lung epithelial cell death and ER stress via CD36. These findings demonstrate that lipotoxicity may have a significant impact on the development of lung injury and fibrosis by enhancing pro-death ER stress pathways.

Endothelial cell (EC) CD36 controls tissue fatty acid (FA) uptake. Here we examine how ECs transfer FAs. FA interaction with apical membrane CD36 induces Src phosphorylation of caveolin-1 tyrosine-14 (Cav-1Y14) and ceramide generation in caveolae. Ensuing fission of caveolae yields vesicles containing FAs, CD36 and ceramide that are secreted basolaterally as small (80–100 nm) exosome-like extracellular vesicles (sEVs). We visualize in transwells EC transfer of FAs in sEVs to underlying myotubes. In mice with EC-expression of the exosome marker emeraldGFP-CD63, muscle fibers accumulate circulating FAs in emGFP-labeled puncta. The FA-sEV pathway is mapped through its suppression by CD36 depletion, blocking actin-remodeling, Src inhibition, Cav-1Y14 mutation, and neutral sphingomyelinase 2 inhibition. Suppression of sEV formation in mice reduces muscle FA uptake, raises circulating FAs, which remain in blood vessels, and lowers glucose, mimicking prominent Cd36 −/ − mice phenotypes. The findings show that FA uptake influences membrane ceramide, endocytosis, and EC communication with parenchymal cells. Endothelial cell CD36 controls tissue fatty acid uptake. Here the authors show how fatty acid uptake by endothelial cells involves regulation of membrane ceramide production, caveolae dynamics, and exosome generation, these events facilitate transfer of circulating fatty acids to tissues and communication between endothelium and parenchyma.

Tumor cells need to rewire their metabolic pathways to regulate the nutrient uptake and metabolism to sustain the energy production. Lipids are important components of energy sources for tumor metabolism. Tumor cells rely on various transporters to mediate the trafficking of lipids for oxidation or activate oncogenic signaling pathways. CD36, a membrane glycoprotein presenting on the surface of cells, binds fatty acids to facilitate their transport for lipid utilization. Upregulated CD36 expression has been observed in multiple cancer types including acute myeloid leukemia, breast cancer, colorectal cancer, gastric cancer, etc. Moreover, CD36 is correlated with poor clinical outcomes and adverse clinicopathological features in various cancer types. In vitro and vivo studies have confirmed that CD36 participates in the regulation of tumor growth, metastasis, drug resistance through diverse molecular mechanisms. Thus, we firstly discussed the role of CD36 in the regulation of metabolic phenotypes, especially in glucose and fatty acid metabolism. Furthermore, we specifically focused on the molecular mechanisms of CD36 in the occurrence and development of multiple tumor types. Collectively, we explored the connection between CD36 and tumors, providing new insights for developing potential therapeutic strategies and tumor stratification targeting CD36.

The diverse expression pattern of CD36 reflects its multiple cellular functions. However, the roles of CD36 in colorectal cancer (CRC) remain unknown. Here, we discover that CD36 expression is progressively decreased from adenomas to carcinomas. CD36 loss predicts poor survival of CRC patients. In CRC cells, CD36 acts as a tumor suppressor and inhibits aerobic glycolysis in vitro and in vivo. Mechanically, CD36-Glypcian 4 (GPC4) interaction could promote the proteasome-dependent ubiquitination of GPC4, followed by inhibition of β-catenin/c-myc signaling and suppression of downstream glycolytic target genes GLUT1, HK2, PKM2 and LDHA. Moreover, disruption of CD36 in inflammation-induced CRC model as well as Apc Min/+ mice model significantly increased colorectal tumorigenesis. Our results reveal a CD36-GPC4-β-catenin-c-myc signaling axis that regulates glycolysis in CRC development and may provide an intervention strategy for CRC prevention. CD36 is a membrane glycoprotein that has been shown to have tumour promoting or suppressor function depending on tumour type. Here, the authors address CD36 function in colorectal cancer and show it acts as a tumour suppressor by inhibiting B-catenin/myc signalling, resulting in downregulation of glycolysis.

Acute infection is known to induce rapid expansion of hematopoietic stem cells (HSCs), but the mechanisms supporting this expansion remain incomplete. Using mouse models, we show that inducible CD36 is required for free fatty acid uptake by HSCs during acute infection, allowing the metabolic transition from glycolysis towards β-oxidation. Mechanistically, high CD36 levels promote FFA uptake, which enables CPT1A to transport fatty acyl chains from the cytosol into the mitochondria. Without CD36-mediated FFA uptake, the HSCs are unable to enter the cell cycle, subsequently enhancing mortality in response to bacterial infection. These findings enhance our understanding of HSC metabolism in the bone marrow microenvironment, which supports the expansion of HSCs during pathogenic challenge. Hematopoietic stem cells (HSCs) rapidly expand upon infection, switching their metabolic profile to increase OXPHOS. Here, the authors show in mouse models that infection promotes uptake of long-chain free fatty acids via CD36, which is required for a protective response.

Movement of circulating fatty acids (FAs) to parenchymal cells requires their transfer across the endothelial cell (EC) barrier. The multiligand receptor cluster of differentiation 36 (CD36) facilitates tissue FA uptake and is expressed in ECs and parenchymal cells such as myocytes and adipocytes. Whether tissue uptake of FAs is dependent on EC or parenchymal cell CD36, or both, is unknown. Using a cell-specific deletion approach, we show that EC, but not parenchymal cell, CD36 deletion increased fasting plasma FAs and postprandial triglycerides. EC-Cd36-KO mice had reduced uptake of radiolabeled long-chain FAs into heart, skeletal muscle, and brown adipose tissue; these uptake studies were replicated using [11C]palmitate PET scans. High-fat diet-fed EC-CD36-deficient mice had improved glucose tolerance and insulin sensitivity. Both EC and cardiomyocyte (CM) deletion of CD36 reduced heart lipid droplet accumulation after fasting, but CM deletion did not affect heart glucose or FA uptake. Expression in the heart of several genes modulating glucose metabolism and insulin action increased with EC-CD36 deletion but decreased with CM deletion. In conclusion, EC CD36 acts as a gatekeeper for parenchymal cell FA uptake, with important downstream effects on glucose utilization and insulin action.

CD36 is a membrane glycoprotein that is present on various types of cells, including monocytes, macrophages, microvascular endothelial cells, adipocytes and platelets. Macrophage CD36 participates in atherosclerotic arterial lesion formation through its interaction with oxidized low-density lipoprotein (oxLDL), which triggers signaling cascades for inflammatory responses. CD36 functions in oxLDL uptake and foam cell formation, which is the initial critical stage of atherosclerosis. In addition, oxLDL via CD36 inhibits macrophage migration, which may be a macrophage-trapping mechanism in atherosclerotic lesions. The role of CD36 was examined in in vitro studies and in vivo experiments, which investigated various functions of CD36 in atherosclerosis and revealed that CD36 deficiency reduces atherosclerotic lesion formation. Platelet CD36 also promotes atherosclerotic inflammatory processes and is involved in thrombus formation after atherosclerotic plaque rupture. Because CD36 is an essential component of atherosclerosis, defining the function of CD36 and its corresponding signaling pathway may lead to a new treatment strategy for atherosclerosis. Atherosclerosis: Multiple roles of membrane protein CD36, a protein found on the surface of various immune cells and blood vessel cells, is a key component of atherosclerosis. Young Mi Park from the Ewha Womans University School of Medicine in Seoul, South Korea, reviews how the CD36 protein on macrophages binds to a form of ‘bad’ cholesterol called oxidized low-density lipoprotein. This binding triggers a series of reactions that leads to inflammation and the formation of foam cells, fat-laden immune cells involved in plaque-build up on the inner lining of blood vessels. CD36 on platelets also promotes inflammatory responses involved in blood clots after plaques rupture. Park argues that a better understanding of CD36 and its functions could lead to new treatments for atherosclerosis, a condition commonly associated with an increased risk of heart attack and stroke.