RESUMEN
Environmental lipids are essential for fueling tumor energetics, but whether these exogenous lipids transported into cancer cells facilitate immune escape remains unclear. Here, we find that CD36, a transporter for exogenous lipids, promotes acute myeloid leukemia (AML) immune evasion. We show that, separately from its established role in lipid oxidation, CD36 on AML cells senses oxidized low-density lipoprotein (OxLDL) to prime the TLR4-LYN-MYD88-nuclear factor κB (NF-κB) pathway, and exogenous palmitate transfer via CD36 further potentiates this innate immune pathway by supporting ZDHHC6-mediated MYD88 palmitoylation. Subsequently, NF-κB drives the expression of immunosuppressive genes that inhibit anti-tumor T cell responses. Notably, high-fat-diet or hypomethylating agent decitabine treatment boosts the immunosuppressive potential of AML cells by hijacking CD36-dependent innate immune signaling, leading to a dampened therapeutic effect. This work is of translational interest because lipid restriction by US Food and Drug Administration (FDA)-approved lipid-lowering statin drugs improves the efficacy of decitabine therapy by weakening leukemic CD36-mediated immunosuppression.
Asunto(s)
Antígenos CD36 , Decitabina , Leucemia Mieloide Aguda , Metabolismo de los Lípidos , Lipoproteínas LDL , Antígenos CD36/metabolismo , Antígenos CD36/genética , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Metabolismo de los Lípidos/efectos de los fármacos , Decitabina/farmacología , Decitabina/uso terapéutico , Lipoproteínas LDL/metabolismo , Animales , FN-kappa B/metabolismo , Línea Celular Tumoral , Factor 88 de Diferenciación Mieloide/metabolismo , Factor 88 de Diferenciación Mieloide/genética , Ratones , Transducción de Señal/efectos de los fármacos , Escape del Tumor/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Receptor Toll-Like 4/metabolismo , Aciltransferasas/genética , Inmunidad Innata/efectos de los fármacos , Ratones Endogámicos C57BLRESUMEN
We reviewed the modern development of clinical application and experimental reseach on the prescription Biejiajian Wan (BJ), which are the basement that we will study its anti-renal fibrosis. At present, the prescription BJ is mainly applied to the treatment of chronic heptic desease. Its experimental reseach is mainly confined to the studing of anti-heptic fibrosi. Refering the scientific and technological result of anti-heptic fibrosis, we think the prescription BJ would have the effection of anti-renal fibrosis on the basis of theory of planning treatment according to diagnosis. But it has not been reported to the prescription BJ on the clinical and experimental reseach on anti-renal fibrosis. Therefore, it is very important to take on clinical reseach of the prescription BJ and discuss the effecting mechanism of anti-renal fibrosis from the level of integration, cell and molecule, which will help to enlarge the clinical application of the prescription Biejiajianwan and explained the essence of "persistent diseases injuring collateral branch of large channel" in traditional Chinese medicine.
