一种用于克服非小细胞肺癌治疗中抗原异质性的多靶向 CAR-T 细胞平台
A Multi-Targeting Chimeric Antigen Receptor-T Cell Platform to Overcome Antigen Heterogeneity in the Treatment of Non-Small Cell Lung Cancer.
这些发现支持采用多靶点CAR-T 策略来应对NSCLC及可能其他实体瘤中的抗原异质性。
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
黄芩素将 CD274/PD-L1 连接至自噬降解以增强抗肿瘤免疫
英文原题：Baicalein tethers CD274/PD-L1 for autophagic degradation to boost antitumor immunity.
查看英文原题
Baicalein tethers CD274/PD-L1 for autophagic degradation to boost antitumor immunity.
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中文摘要
免疫检查点抑制剂，尤其是靶向CD274/PD-L1的抑制剂，可产生强大的临床治疗效果。尽管基于抗体的CD274药物开发已取得很大进展，但用于CD274降解的化学化合物在很大程度上仍不可获得。
在此，我们筛选并验证了黄芩素，一种中药单体，可靶向CD274并诱导其巨自噬/自噬降解。此外，我们证明CD274直接与MAP1LC3B（微管相关蛋白1轻链3β）相互作用。有趣的是，黄芩素增强CD274-LC3相互作用，以促进CD274的自噬-溶酶体降解。
重要的是，通过黄芩素靶向CD274降解，通过增强T细胞介导的抗肿瘤免疫来抑制肿瘤发展。因此，我们阐明了自噬-溶酶体途径在介导CD274降解中的关键作用，并从概念上证明，设计一种将CD274-LC3相互作用连接起来的分子“胶水”是开发癌症治疗中CD274抑制剂的一种有吸引力的策略。
缩写：ATTECs：自噬连接化合物；AUTACs：自噬靶向嵌合体；AUTOTACs：自噬靶向嵌合体；AMPK：腺苷5‘-单磷酸（AMP）活化蛋白激酶；BiFC：双分子荧光互补；BafA1：巴弗洛霉素A1；CD274/PD-L1/B7-H1：CD274分子；CQ：氯喹；CGAS：环GMP-AMP合酶；DAPI：4’6-二氨基-2-苯基吲哚；FITC：异硫氰酸荧光素异构体；GFP：绿色荧光蛋白；GZMB：颗粒酶B；IHC：免疫组织化学；ICB：免疫检查点阻断；KO：敲除；KD：平衡解离常数；LYTAC：溶酶体靶向嵌合体；LIR：LC3相互作用区域；MAP1LC3/LC3：微管相关蛋白1轻链3；MST：微量热泳动；NFAT：活化T细胞核因子；NFKB/NF-kB：核因子kappa B；NSCLC：非小细胞肺癌；PDCD1：程序性细胞死亡1；PROTACs：蛋白水解靶向嵌合体；PRF1：穿孔素1；PE：磷脂酰乙醇胺；PHA：植物血凝素；PMA：佛波醇12-肉豆蔻酸酯13-乙酸酯；STAT：信号转导及转录激活因子；SPR：表面等离子体共振；TILs：TIL（肿瘤浸润淋巴细胞）；TME：肿瘤微环境。
展开英文摘要原文
Immune checkpoint inhibitors, especially those targeting CD274/PD-L1yield powerful clinical therapeutic efficacy. Thoughmuch progress has been made in the development of antibody-basedCD274 drugs, chemical compounds applied for CD274degradation remain largely unavailable.
Herein,baicalein, a monomer of traditional Chinese medicine, isscreened and validated to target CD274 and induces itsmacroautophagic/autophagic degradation.
Moreover, we demonstrate thatCD274 directly interacts with MAP1LC3B (microtubule associatedprotein 1 light chain 3 beta). Intriguingly, baicalein potentiatesCD274-LC3 interaction to facilitate autophagic-lysosomal degradationof CD274.
Importantly, targeted CD274. degradation via baicaleininhibits tumor development by boosting T-cell-mediated antitumorimmunity.
Thus, we elucidate a critical role of autophagy-lysosomalpathway in mediating CD274 degradation, and conceptually demonstratethat the design of a molecular "glue" that tethers the CD274-LC3interaction is an appealing strategy to develop CD274 inhibitors incancer therapy.
Abbreviations : ATTECs: autophagy-tethering compounds; AUTACs: AUtophagy-TArgeting Chimeras; AUTOTACs: AUTOphagy-TArgeting Chimeras; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; BiFC: bimolecular fluorescence complementation; BafA1: bafilomycin A 1 ; CD274/PD-L1/B7-H1: CD274 molecule; CQ: chloroquine; CGAS: cyclic GMP-AMP synthase; DAPI: 4'6-diamino-2-phenylindole; FITC: fluorescein isothiocyanate isomer; GFP: green fluorescent protein; GZMB: granzyme B; IHC: immunohistochemistry; ICB: immune checkpoint blockade; KO: knockout; KD: equilibrium dissociation constant; LYTAC: LYsosome-TArgeting Chimera; LIR: LC3-interacting region; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MST: microscale thermophoresis; NFAT: nuclear factor of activated T cells; NFKB/NF-kB: nuclear factor kappa B; NSCLC: non-small-cell lung cancer; PDCD1: programmed cell death 1; PROTACs: PROteolysis TArgeting Chimeras; PRF1: perforin 1; PE: phosphatidylethanolamine; PHA: phytohemagglutinin; PMA: phorbol 12-myristate 13-acetate; STAT: signal transducer and activator of transcription; SPR: surface plasmon resonance; TILs: tumor-infiltrating lymphocyte; TME: tumor microenvironment.
论文信息
- 作者
- Hao B、Lin S、Liu H、Xu J、Chen L、Zheng T、Zhang W、Dang Y
- 单位
- Institute of Energy Metabolism and Health, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.China
- 文献类型
- 非美国政府资助研究
- 期刊
- Autophagy2025 May
- 原文标识
- PubMed 39710370 · DOI 10.1080/15548627.2024.2439657
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