PO.MCB07.02 · 分子与细胞生物学
翻译起始因子CTIF的先导翻译轮次调控耐药持留细胞的肿瘤免疫
Pioneer round of translation factor CTIF regulates tumor immunity in drug-tolerant persister cells
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：肿瘤细胞可塑性使癌细胞能够通过协调的表观遗传、转录和翻译变化改变其表型。耐药持留细胞（DTP）代表一种与治疗抵抗和微小残留病（MRD）相关的关键可塑性状态。新合成的mRNA经历先导翻译轮次（PRT）以进行质量控制，然而PRT如何影响肿瘤可塑性和免疫逃逸仍属未知。我们假设PRT相关的起始因子CTIF——CBP80-CBP20依赖性翻译机器的核心组分——调控DTP的免疫抑制表型，并促成MRD相关的免疫逃逸。
方法：我们整合了LUAD、BRCA、SKCM和COAD的bulk RNA-seq数据集，以定义跨癌种的DTP转录特征。我们在多种癌种中建立了DTP模型和同源CTIF敲低（KD）细胞。我们通过多聚核糖体分析和核糖体测序（Ribo-seq）检测了PRT相关因子表达、药物IC50、增殖和翻译输出。使用同基因免疫健全和免疫缺陷模型在体内评估了CTIF的功能相关性。
结果：跨癌种分析揭示了治疗特异性的DTP特征，并汇聚于共有通路，包括CTIF和其他PRT相关因子的表达改变。CTIF-KD在体外对耐药性或增殖影响甚微，但多聚核糖体分析和Ribo-seq表明核糖体翻译景观发生改变。整合的RNA-seq和Ribo-seq证明CTIF-KD在翻译水平上选择性上调免疫相关转录本，提示其在免疫调节中具有此前未被认识的作用。在体内，CTIF-KD不影响免疫缺陷小鼠的肿瘤生长，但显著抑制免疫健全宿主的肿瘤进展，与增强的免疫识别相一致。
结论：我们的研究揭示了CTIF的一种非经典的免疫调节作用。尽管CTIF在体外对增殖和耐药是可有可无的，但它以免疫依赖性方式对体内肿瘤生长至关重要。我们提出CTIF塑造肿瘤翻译组以维持免疫逃逸，而靶向PRT，尤其是CTIF，可能提供一种克服免疫抑制并清除肿瘤免疫微环境内MRD相关持留状态的新策略。
查看英文原文 English abstract
Background: Tumor cell plasticity enables cancer cells to alter their phenotype through coordinated epigenetic, transcriptional, and translational changes. Drug-tolerant persister cells (DTPs) represent a key plastic state associated with therapy resistance and minimal residual disease (MRD). Newly synthesized mRNAs undergo a pioneer round of translation (PRT) for quality control, yet how PRT influences tumor plasticity and immune evasion remains unknown. We hypothesize that the PRT-associated initiation factor CTIF, a core component of CBP80-CBP20-dependent translation machinery, regulates the immunosuppressive phenotype of DTPs and contributes to MRD-associated immune escape.
Methods: We integrated the bulk RNA-seq datasets across LUAD, BRCA, SKCM and COAD to define cross-cancer DTP transcriptional features. DTP models and isogenic CTIF-knockdown (KD) cells were established across multiple cancer types. We examined PRT-related factor expression, drug IC50, proliferation, and translational output via polysome profile and ribosome sequencing (Ribo-seq). Functional relevance of CTIF was evaluated in vivo using syngeneic immunocompetent and immunodeficient models.
Results: Cross-cancer analyses revealed treatment-specific DTP signatures with convergence on shared pathways, including altered expression of CTIF and additional PRT-related factors. CTIF-KD had minimal effects on drug resistance or proliferation in vitro, but polysome profiling and Ribo-seq indicated altered ribosome translation landscape. Integrated RNA-seq and Ribo-seq demonstrated that CTIF-KD selectively upregulated immune-related transcripts at the translational level, suggesting a previously unrecognized role in immune modulation. In vivo, CTIF-KD did not affect tumor growth in immunodeficient mice but significantly impaired tumor progression in immunocompetent hosts, consistent with enhanced immune recognition.
Conclusions: Our study uncovers a non-canonical, immune-regulatory role of CTIF. Although dispensable for proliferation and drug tolerance in vitro, CTIF is essential for tumor growth in vivo in an immune-dependent manner. We propose that CTIF shapes the tumor translatome to sustain immune evasion, and that targeting PRT, particularly CTIF, may offer a novel strategy to overcome immune suppression and eliminate MRD-associated persister states within the tumor immune microenvironment.
利益披露 Disclosure
Y. Wang, None..
M. Wang, None..
K. Li, None..
S. Shen, None.