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Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD 白细胞介素-21 工程通过 CEBPD 增强 NK 细胞抗胶质母细胞瘤的活性
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.007
Glioblastoma (GBM) is an aggressive brain cancer with limited therapeutic options. Natural killer (NK) cells are innate immune cells with strong anti-…
胶质母细胞瘤(GBM)是一种侵袭性脑癌,治疗方案有限。自然杀伤(NK)细胞是一种先天性免疫细胞,具有很强的抗...
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引用次数: 0
Leading medulloblastoma to a differentiation end 引导髓母细胞瘤走向分化的终点
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.011

Effective and less toxic therapies for medulloblastoma have proved to be highly elusive. In this issue of Cancer Cell, Yang et al. show that thyroid hormone treatment leads to the activation of neurogenic differentiation factor 1 (NeuroD1) and differentiation of medulloblastoma cells through reversing EZH2-mediated transcriptional repression of NeuroD1.

事实证明,治疗髓母细胞瘤的有效且低毒的疗法非常难以捉摸。在本期《癌细胞》(Cancer Cell)杂志上,Yang等人发现,甲状腺激素治疗可通过逆转EZH2介导的NeuroD1转录抑制,导致神经源分化因子1(NeuroD1)的激活和髓母细胞瘤细胞的分化。
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引用次数: 0
When playing the NK cell therapy card in glioblastoma, you can’t beat interleukin-21 在胶质母细胞瘤中使用 NK 细胞疗法时,白细胞介素-21 是不可或缺的。
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.003

Glioblastoma is the most common brain cancer, with a 5-year survival rate of less than 10%. This grim prognosis highlights the urgent need for novel therapeutic approaches. In this issue of Cancer Cell, Shanley et al.1 report an innovative engineering strategy to supercharge NK cell immunity against glioblastoma.

胶质母细胞瘤是最常见的脑癌,5 年生存率不到 10%。这种严峻的预后凸显了对新型治疗方法的迫切需求。在本期《癌细胞》(Cancer Cell)杂志上,Shanley 等人1 报告了一种创新的工程策略,它能增强 NK 细胞对胶质母细胞瘤的免疫力。
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引用次数: 0
Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells 甲状腺激素通过促进肿瘤细胞的终末分化抑制髓母细胞瘤的发展
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.008

Hypothyroidism is commonly detected in patients with medulloblastoma (MB). However, whether thyroid hormone (TH) contributes to MB pathogenicity remains undetermined. Here, we find that TH plays a critical role in promoting tumor cell differentiation. Reduction in TH levels frees the TH receptor, TRα1, to bind to EZH2 and repress expression of NeuroD1, a transcription factor that drives tumor cell differentiation. Increased TH reverses EZH2-mediated repression of NeuroD1 by abrogating the binding of EZH2 and TRα1, thereby stimulating tumor cell differentiation and reducing MB growth. Importantly, TH-induced differentiation of tumor cells is not restricted by the molecular subgroup of MB, suggesting that TH can be used to broadly treat MB subgroups. These findings establish an unprecedented association between TH signaling and MB pathogenicity, providing solid evidence for TH as a promising modality for MB treatment.

髓母细胞瘤(MB)患者通常会出现甲状腺功能减退。然而,甲状腺激素(TH)是否会导致髓母细胞瘤的致病性仍未确定。在这里,我们发现甲状腺激素在促进肿瘤细胞分化方面起着关键作用。TH水平的降低会释放TH受体TRα1,使其与EZH2结合并抑制NeuroD1的表达,而NeuroD1是一种转录因子,可驱动肿瘤细胞分化。增加的 TH 可通过抑制 EZH2 和 TRα1 的结合来逆转 EZH2 介导的 NeuroD1 抑制,从而刺激肿瘤细胞分化并减少 MB 的生长。重要的是,TH 诱导的肿瘤细胞分化不受 MB 分子亚群的限制,这表明 TH 可用于广泛治疗 MB 亚群。这些发现在 TH 信号传导与 MB 致病性之间建立了前所未有的联系,为 TH 作为一种有前途的 MB 治疗方式提供了确凿证据。
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引用次数: 0
Effect of neoadjuvant chemoradiotherapy with or without PD-1 antibody sintilimab in pMMR locally advanced rectal cancer: A randomized clinical trial 新辅助化放疗联合或不联合 PD-1 抗体 sintilimab 对 pMMR 局部晚期直肠癌的疗效:随机临床试验
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-08-01 DOI: 10.1016/j.ccell.2024.07.004

Neoadjuvant chemoradiotherapy (NACRT) was the standard treatment for patients with locally advanced rectal cancer (LARC) with proficient mismatch repair (pMMR) proteins. In this randomized phase 2 trial (ClinicalTrial.gov: NCT04304209), 134 pMMR LARC patients were randomly (1:1) assigned to receive NACRT or NACRT and the programmed cell death protein 1 (PD-1) antibody sintilimab. As the primary endpoint, the total complete response (CR) rate is 26.9% (18/67, 95% confidence interval [CI] 16.0%–37.8%) and 44.8% (30/67, 95% CI 32.6%–57.0%) in the control and experimental arm, respectively, with significant difference (p = 0.031 for chi-squared test). Response ratio is 1.667 (95% CI 1.035–2.683). Immunohistochemistry shows PD-1 ligand 1 (PD-L1) combined positive score is associated with the synergistic effect. The safety profile is similar between the arms. Adding the PD-1 antibody sintilimab to NACRT significantly increases the CR rate in pMMR LARC, with a manageable safety profile. PD-L1 positivity may help identify patients who might benefit most from the combination therapy.

新辅助化放疗(NACRT)是针对具有熟练错配修复(pMMR)蛋白的局部晚期直肠癌(LARC)患者的标准治疗方法。在这项随机2期试验(ClinicalTrial.gov: NCT04304209)中,134名pMMR LARC患者被随机(1:1)分配接受NACRT或NACRT和程序性细胞死亡蛋白1(PD-1)抗体sintilimab治疗。作为主要终点,对照组和实验组的总完全应答率(CR)分别为26.9%(18/67,95% 置信区间 [CI] 16.0%-37.8%)和44.8%(30/67,95% CI 32.6%-57.0%),差异显著(卡方检验 p = 0.031)。反应比为 1.667(95% CI 1.035-2.683)。免疫组化显示,PD-1配体1(PD-L1)联合评分阳性与协同效应有关。两组患者的安全性相似。在NACRT中加入PD-1抗体sintilimab可显著提高pMMR LARC的CR率,且安全性可控。PD-L1 阳性可能有助于识别从联合疗法中获益最多的患者。
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引用次数: 0
Longitudinal on-treatment circulating tumor DNA as a biomarker for real-time dynamic risk monitoring in cancer patients: The EP-SEASON study 将纵向治疗循环肿瘤 DNA 作为生物标记物,对癌症患者进行实时动态风险监测:EP-SEASON研究
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-07-25 DOI: 10.1016/j.ccell.2024.07.001

Recurrence risks of cancer patient can change during treatment as a result of treatment-related tumor evolution. However, biomarkers that can monitor these changes are lacking. Here, we investigated whether tracking circulating tumor DNA (ctDNA) dynamics through liquid biopsy can inform real-time recurrence risk. Nasopharyngeal carcinoma (NPC) provides an ideal model where cell-free Epstein-Barr virus (EBV) DNA (cfEBV DNA), a ctDNA, can be sensitively detected. We conducted the EP-SEASON study (NCT03855020) and prospectively recruited 1,000 NPC patients undergoing per-protocol cfEBV DNA assessments at 11 time points and receiving sequential chemo-radiotherapy. Longitudinal cfEBV DNA displayed distinct patterns during neoadjuvant chemotherapy and radiotherapy. Despite the prognostic significance of cfEBV DNA at each time point, real-time recurrence risks changed in sync with cfEBV DNA dynamics. Furthermore, we identified phenotypes of whole-course ctDNA changing dynamics associated with different survival outcomes. In conclusion, tracking longitudinal on-treatment ctDNA can forecast real-time recurrence risk, facilitating risk-adapted, individualized patient management.

癌症患者的复发风险会在治疗过程中因与治疗相关的肿瘤演变而发生变化。然而,目前还缺乏能监测这些变化的生物标记物。在此,我们研究了通过液体活检跟踪循环肿瘤DNA(ctDNA)动态是否能为实时复发风险提供信息。鼻咽癌(NPC)提供了一个理想的模型,可以灵敏地检测细胞游离爱泼斯坦-巴氏病毒(EBV)DNA(cfEBV DNA)(一种ctDNA)。我们开展了EP-SEASON研究(NCT03855020),前瞻性地招募了1000名鼻咽癌患者,在11个时间点按协议进行cfEBV DNA评估,并接受连续化疗和放疗。在新辅助化疗和放疗期间,纵向cfEBV DNA显示出不同的模式。尽管每个时间点的cfEBV DNA都具有预后意义,但实时复发风险与cfEBV DNA的动态变化同步。此外,我们还发现了与不同生存结果相关的全病程ctDNA动态变化表型。总之,追踪治疗过程中的纵向ctDNA可以预测实时复发风险,从而促进适应风险的个体化患者管理。
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引用次数: 0
CAR T cell combination therapies to treat cancer 治疗癌症的 CAR T 细胞组合疗法
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-07-25 DOI: 10.1016/j.ccell.2024.07.002

Chimeric antigen receptor (CAR) T cells are effectively used in certain hematological malignancies, though tumor relapse and limited success in solid tumors persist. Recent efforts focus on developing combination treatments to enhance outcomes and safety. Here, we provide a comprehensive overview of such combinatorial approaches and a consideration of ongoing clinical trials.

嵌合抗原受体(CAR)T 细胞在某些血液恶性肿瘤中得到了有效应用,但在实体瘤中仍存在肿瘤复发和成功率有限的问题。最近的研究重点是开发联合疗法,以提高疗效和安全性。在此,我们将全面概述此类组合方法,并考虑正在进行的临床试验。
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引用次数: 0
Tumor-infiltrating lymphocytes: A new hope 肿瘤浸润淋巴细胞:新希望
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-07-18 DOI: 10.1016/j.ccell.2024.06.015

Tumor-infiltrating lymphocytes (TILs) can be massively expanded from resected tumors and used as a cellular treatment for advanced malignancies. TILs require a preparative non-myeloablative chemotherapy followed by an abbreviated course of interleukin-2. Here, we review the historical development of TIL therapy and discuss potential solutions to ongoing roadblocks that may result in broader and improved efficacy for patients afflicted with treatment-refractory, advanced cancer.

肿瘤浸润淋巴细胞(TILs)可以从切除的肿瘤中大量扩增,并用作晚期恶性肿瘤的细胞治疗。TIL需要先进行非减低瘤细胞数量的化疗,然后再使用白细胞介素-2的简短疗程。在此,我们回顾了TIL疗法的历史发展,并讨论了解决当前障碍的潜在方案,这些方案可能会为难治性晚期癌症患者带来更广泛、更高的疗效。
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引用次数: 0
Transcription factor dependencies identify BAF-dependent cancers 转录因子依赖性确定了 BAF 依赖性癌症
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-07-18 DOI: 10.1016/j.ccell.2024.06.013

In Cancer Cell, Bolomsky et al., Duplaquet et al., and He et al. identify cancers that are dependent on the BAF chromatin remodeling complex, specifically IRF4-driven multiple myeloma and POU2F3-subtype small cell lung cancer, highlighting potential therapeutic applications for BAF complex inhibitors/degraders.

在《癌症细胞》(Cancer Cell)杂志上,Bolomsky 等人、Duplaquet 等人和 He 等人发现了依赖 BAF 染色质重塑复合物的癌症,特别是 IRF4 驱动的多发性骨髓瘤和 POU2F3 亚型小细胞肺癌,突出了 BAF 复合物抑制剂/降解剂的潜在治疗应用。
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引用次数: 0
Mammalian SWI/SNF complex activity regulates POU2F3 and constitutes a targetable dependency in small cell lung cancer 哺乳动物 SWI/SNF 复合物活性调控 POU2F3 并构成小细胞肺癌的靶向依赖性
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-07-18 DOI: 10.1016/j.ccell.2024.06.012

Small cell lung cancers (SCLCs) are composed of heterogeneous subtypes marked by lineage-specific transcription factors, including ASCL1, NEUROD1, and POU2F3. POU2F3-positive SCLCs, ∼12% of all cases, are uniquely dependent on POU2F3 itself; as such, approaches to attenuate POU2F3 expression may represent new therapeutic opportunities. Here using genome-scale screens for regulators of POU2F3 expression and SCLC proliferation, we define mSWI/SNF complexes as top dependencies specific to POU2F3-positive SCLC. Notably, chemical disruption of mSWI/SNF ATPase activity attenuates proliferation of all POU2F3-positive SCLCs, while disruption of non-canonical BAF (ncBAF) via BRD9 degradation is effective in pure non-neuroendocrine POU2F3-SCLCs. mSWI/SNF targets to and maintains accessibility over gene loci central to POU2F3-mediated gene regulatory networks. Finally, clinical-grade pharmacologic disruption of SMARCA4/2 ATPases and BRD9 decreases POU2F3-SCLC tumor growth and increases survival in vivo. These results demonstrate mSWI/SNF-mediated governance of the POU2F3 oncogenic program and suggest mSWI/SNF inhibition as a therapeutic strategy for POU2F3-positive SCLCs.

小细胞肺癌(SCLCs)由异质性亚型组成,其特征是存在特异性转录因子,包括ASCL1、NEUROD1和POU2F3。POU2F3阳性的SCLC(占所有病例的12%)对POU2F3本身具有独特的依赖性;因此,减少POU2F3表达的方法可能代表着新的治疗机会。在这里,我们利用基因组规模的筛选来寻找POU2F3表达和SCLC增殖的调控因子,并将mSWI/SNF复合物定义为POU2F3阳性SCLC特有的最高依赖性。值得注意的是,通过化学方法破坏 mSWI/SNF ATPase 的活性可减轻所有 POU2F3 阳性 SCLC 的增殖,而通过 BRD9 降解破坏非典型 BAF (ncBAF) 则对纯合的非神经内分泌 POU2F3-SCLC 有效。最后,对SMARCA4/2 ATP酶和BRD9进行临床级别的药理干扰可减少POU2F3-SCLC肿瘤的生长并提高体内存活率。这些结果证明了mSWI/SNF介导的POU2F3致癌程序的治理,并建议将mSWI/SNF抑制作为POU2F3阳性SCLC的治疗策略。
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Cancer Cell
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