谷氨酰胺分解
癌症免疫疗法
免疫系统
谷氨酰胺酶
癌细胞
细胞毒性T细胞
免疫疗法
化学
癌症研究
谷氨酰胺
琥珀酸脱氢酶
肿瘤微环境
癌症
生物化学
细胞生物学
生物
免疫学
医学
酶
内科学
氨基酸
体外
作者
Sahil Inamdar,Abhirami P. Suresh,Joslyn L. Mangal,Nathan D. Ng,Alison Sundem,Hoda Shokrollahzadeh Behbahani,Thomas Rubino,Xiaojian Shi,Sharon T. Loa,Jordan R. Yaron,Taro Hitosugi,Matthew Green,Haiwei Gu,Marion Curtis,Abhinav P. Acharya
标识
DOI:10.1016/j.jconrel.2023.05.014
摘要
Boosting the metabolism of immune cells while restricting cancer cell metabolism is challenging. Herein, we report that using biomaterials for the controlled delivery of succinate metabolite to phagocytic immune cells activates them and modulates their metabolism in the presence of metabolic inhibitors. In young immunocompetent mice, polymeric microparticles, with succinate incorporated in the backbone, induced strong pro-inflammatory anti-melanoma responses. Administration of poly(ethylene succinate) (PES MP)-based vaccines and glutaminase inhibitor to young immunocompetent mice with aggressive and large, established B16F10 melanoma tumors increased their survival three-fold, a result of increased cytotoxic T cells expressing RORγT (Tc17). Mechanistically, PES MPs directly modulate glutamine and glutamate metabolism, upregulate succinate receptor SUCNR1, activate antigen presenting cells through and HIF-1alpha, TNFa and TSLP-signaling pathways, and are dependent on alpha-ketoglutarate dehydrogenase for their activity, which demonstrates correlation of succinate delivery and these pathways. Overall, our findings suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.
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