PO.CL06.03 · 临床研究
用TAK-981靶向MYC-SUMO轴逆转免疫抑制并恢复骨肉瘤中的抗原呈递
Targeting the MYC-SUMO axis with TAK-981 reverses immune suppression and restores antigen presentation in osteosarcoma
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摘要 Abstract
中文摘要
背景：骨肉瘤（OS）是青少年中最常见的原发性骨癌，由于其侵袭性生长、早期转移以及对免疫治疗反应差，仍然难以治疗。约20-30%的OS存在8q24扩增，导致MYC过表达和免疫冷肿瘤微环境（TME）。为了研究MYC驱动的免疫逃逸，我们构建了一个成骨细胞特异性的Myc敲入GEMM，并进行了互补性的机制研究。
方法：通过组织病理学、生长动力学、免疫分析（流式细胞术、IHC）、Western印迹和RNA-seq对Myc敲入模型进行表征。在GEMM肿瘤、OS PDX和公共数据集中评估了抗原呈递机制（APM）基因表达。使用dTAG降解和siRNA敲低测试MYC依赖性。由于MYC与SUMO依赖性抑制相关，我们使用SAE抑制剂TAK-981和SAE1敲低检查了SUMO通路。SUMO相互作用组分析（SUMO-IP/MS）确定了MYC相关的SUMO底物。
结果：MYC敲入GEMM发展出快速进展且高度转移的OS，在转录层面上类似于MYC高表达的人OS。MYC激活产生了强烈免疫抑制的TME，CD45⁺细胞减少和广泛的APM抑制。MYC丢失恢复了APM表达，确立了MYC作为抗原呈递的关键抑制因子。SUMO化机制（SUMO1/2、SAE1/2、UBC9）在MYC高表达模型中升高，并与APM呈负相关。TAK-981在体外表现出强效的MYC选择性细胞毒性，在小鼠和PDX细胞系中MYC高表达细胞比MYC低表达对应细胞敏感得多。TAK-981还减少了增殖、迁移和球体形成。在体内，TAK-981在同基因和PDX模型中均显著抑制肿瘤生长。转录组学揭示了MYC靶标、EMT、糖酵解和G2/M信号的减少，同时诱导了IFN-alpha/gamma通路、炎症反应和APM基因。SUMO-IP/MS确定了MYC调控的SUMO相互作用蛋白，包括G3BP1/2、TARDBP、EIF3D和PSMD4，提示了SUMO依赖性免疫逃避机制。将TAK-981与STING激动剂联合使用产生了协同的肿瘤控制，实现了近乎完全的反应。
结论：MYC通过SUMO依赖性抑制抗原呈递和固有免疫通路来驱动OS中的免疫抑制。用TAK-981靶向MYC-SUMO轴将TME从免疫冷转变为免疫炎症，并增强免疫治疗反应，支持基于TAK-981的联合疗法作为MYC驱动OS的一种有前景的策略。
查看英文原文 English abstract
Background: Osteosarcoma (OS), the most common primary bone cancer in adolescents, remains difficult to treat due to aggressive growth, early metastasis, and poor response to immunotherapy. About 20-30% of OS harbor 8q24 amplification, causing MYC overexpression and an immune-cold tumor microenvironment (TME). To investigate MYC-driven immune evasion, we generated an osteoblast-specific Myc-knockin GEMM and performed complementary mechanistic studies.
Methods: The Myc-knockin model was characterized through histopathology, growth kinetics, immune profiling (flow cytometry, IHC), Western blotting, and RNA-seq. Antigen-presentation machinery (APM) gene expression was assessed in GEMM tumors, OS PDXs, and public datasets. MYC dependence was tested using dTAG degradation and siRNA knockdown. Because MYC is linked to SUMO-dependent repression, we examined the SUMO pathway using the SAE inhibitor TAK-981 and SAE1 knockdown. SUMO-interactome profiling (SUMO-IP/MS) identified MYC-associated SUMO substrates.
Results: The MYC-knockin GEMM developed rapidly progressive and highly metastatic OS that transcriptionally resembled MYC-high human OS. MYC activation produced a strongly immunosuppressive TME with reduced CD45⁺ cells and broad APM repression. MYC loss restored APM expression, establishing MYC as a key inhibitor of antigen presentation. SUMOylation machinery (SUMO1/2, SAE1/2, UBC9) was elevated in MYC-high models and inversely correlated with APM. TAK-981 showed potent MYC-selective cytotoxicity in vitro, with MYC-high cells far more sensitive than MYC-low counterparts across mouse and PDX lines. TAK-981 also reduced proliferation, migration, and sphere formation. In vivo, TAK-981 significantly suppressed tumor growth across syngeneic and PDX models. Transcriptomics revealed reduced MYC targets, EMT, glycolysis, and G2/M signaling, alongside induction of IFN-alpha/gamma pathways, inflammatory responses, and APM genes. SUMO-IP/MS identified MYC-regulated SUMO-interacting proteins, including G3BP1/2, TARDBP, EIF3D, and PSMD4, implicating SUMO-dependent immune-evasion mechanisms. Combining TAK-981 with a STING agonist produced synergistic tumor control, achieving near-complete responses.
Conclusions: MYC drives immune suppression in OS through SUMO-dependent repression of antigen-presentation and innate immune pathways. Targeting the MYC-SUMO axis with TAK-981 converts the TME from immune-cold to immune-inflamed and enhances immunotherapy responses, supporting TAK-981-based combinations as a promising strategy for MYC-driven OS.
利益披露 Disclosure
B. K. Nirala, None..
T. Yamamichi, None..
R. Tsukada, None.