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A highly sensitive reporter system to monitor endogenous YAP1/TAZ activity and its application in various human cells 用于监测内源性 YAP1/TAZ 活性的高灵敏度报告系统及其在各种人类细胞中的应用。
IF 4.5 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-18 DOI: 10.1111/cas.16316
Hiroki Hikasa, Kohichi Kawahara, Masako Inui, Yukichika Yasuki, Keita Yamashita, Kohei Otsubo, Shojiro Kitajima, Miki Nishio, Kazunari Arima, Motoyoshi Endo, Masanori Taira, Akira Suzuki

The activation of yes-associated protein 1 (YAP1) and transcriptional co-activator with PDZ-binding motif (TAZ) has been implicated in both regeneration and tumorigenesis, thus representing a double-edged sword in tissue homeostasis. However, how the activity of YAP1/TAZ is regulated or what leads to its dysregulation in these processes remains unknown. To explore the upstream stimuli modulating the cellular activity of YAP1/TAZ, we developed a highly sensitive YAP1/TAZ/TEAD-responsive DNA element (YRE) and incorporated it into a lentivirus-based reporter cell system to allow for sensitive and specific monitoring of the endogenous activity of YAP1/TAZ in terms of luciferase activity in vitro and Venus fluorescence in vivo. Furthermore, by replacing YRE with TCF- and NF-κB-binding DNA elements, we demonstrated the applicability of this reporter system to other pathways such as Wnt/β-catenin/TCF- and IL-1β/NF-κB-mediated signaling, respectively. The practicality of this system was evaluated by performing cell-based reporter screening of a chemical compound library consisting of 364 known inhibitors, using reporter-introduced cells capable of quantifying YAP1/TAZ- and β-catenin-mediated transcription activities, which led to the identification of multiple inhibitors, including previously known as well as novel modulators of these signaling pathways. We further confirmed that novel YAP1/TAZ modulators, such as potassium ionophores, Janus kinase inhibitors, platelet-derived growth factor receptor inhibitors, and genotoxic stress inducers, alter the protein level or phosphorylation of endogenous YAP1/TAZ and the expression of their target genes. Thus, this reporter system provides a powerful tool to monitor endogenous signaling activities of interest (even in living cells) and search for modulators in various cellular contexts.

是相关蛋白1(YAP1)和具有PDZ结合基调的转录协同激活因子(TAZ)的激活与再生和肿瘤发生都有关系,因此是组织稳态的一把双刃剑。然而,在这些过程中,YAP1/TAZ的活性是如何被调控的,或导致其失调的原因是什么,目前仍不得而知。为了探索调控 YAP1/TAZ 细胞活性的上游刺激因素,我们开发了一种高灵敏度的 YAP1/TAZ/TEAD 响应 DNA 元件(YRE),并将其整合到基于慢病毒的报告细胞系统中,从而可以通过体外荧光素酶活性和体内维纳斯荧光灵敏而特异地监测 YAP1/TAZ 的内源性活性。此外,通过用TCF和NF-κB结合DNA元件取代YRE,我们证明了该报告系统适用于其他途径,如Wnt/β-catenin/TCF和IL-1β/NF-κB介导的信号传导。通过使用能量化 YAP1/TAZ 和 β-catenin 介导的转录活性的报告基因导入细胞,对由 364 种已知抑制剂组成的化合物库进行基于细胞的报告基因筛选,评估了该系统的实用性。我们进一步证实,新型 YAP1/TAZ 调节剂(如钾离子诱导剂、Janus 激酶抑制剂、血小板衍生生长因子受体抑制剂和基因毒性应激诱导剂)会改变内源性 YAP1/TAZ 的蛋白水平或磷酸化及其靶基因的表达。因此,这种报告系统为监测感兴趣的内源性信号活动(甚至在活细胞中)和寻找各种细胞环境中的调节剂提供了一种强有力的工具。
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引用次数: 0
Chromatin lysine acylation: On the path to chromatin homeostasis and genome integrity 染色质赖氨酸酰化:染色质平衡与基因组完整性之路
IF 4.5 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-18 DOI: 10.1111/cas.16321
Feng Chen, Xingkai He, Wenchao Xu, Linmin Zhou, Qi Liu, Weicheng Chen, Wei-Guo Zhu, Jun Zhang

The fundamental role of cells in safeguarding the genome's integrity against DNA double-strand breaks (DSBs) is crucial for maintaining chromatin homeostasis and the overall genomic stability. Aberrant responses to DNA damage, known as DNA damage responses (DDRs), can result in genomic instability and contribute significantly to tumorigenesis. Unraveling the intricate mechanisms underlying DDRs following severe damage holds the key to identify therapeutic targets for cancer. Chromatin lysine acylation, encompassing diverse modifications such as acetylation, lactylation, crotonylation, succinylation, malonylation, glutarylation, propionylation, and butyrylation, has been extensively studied in the context of DDRs and chromatin homeostasis. Here, we delve into the modifying enzymes and the pivotal roles of lysine acylation and their crosstalk in maintaining chromatin homeostasis and genome integrity in response to DDRs. Moreover, we offer a comprehensive perspective and overview of the latest insights, driven primarily by chromatin acylation modification and associated regulators.

细胞在保护基因组完整性、防止 DNA 双链断裂(DSB)方面发挥着基础性作用,这对维持染色质平衡和基因组整体稳定性至关重要。对DNA损伤的异常反应,即DNA损伤反应(DDR),可导致基因组不稳定,并在很大程度上导致肿瘤发生。揭示严重损伤后 DDRs 的复杂机制是确定癌症治疗靶点的关键。染色质赖氨酸酰化包括乙酰化、乳酰化、巴豆酰化、琥珀酰化、丙二酰化、谷氨酰化、丙酰化和丁酰化等多种修饰,在 DDRs 和染色质稳态的背景下已被广泛研究。在这里,我们深入研究了赖氨酸酰化的修饰酶和关键作用,以及它们在应对 DDRs 过程中维持染色质稳态和基因组完整性的相互关系。此外,我们还从全面的角度概述了主要由染色质酰化修饰和相关调节因子驱动的最新见解。
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引用次数: 0
Fusobacterium nucleatum, immune responses, and metastatic organ diversity in colorectal cancer liver metastasis 大肠癌肝转移中的核酸梭菌、免疫反应和转移器官多样性
IF 4.5 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-14 DOI: 10.1111/cas.16315
Yasuyuki Shigematsu, Rumiko Saito, Gulanbar Amori, Hiroaki Kanda, Yu Takahashi, Kengo Takeuchi, Shunji Takahashi, Kentaro Inamura

The presence of Fusobacterium nucleatum is associated with an immunosuppressive tumor immune microenvironment (TIM) in primary colorectal cancer (CRC), contributing to tumor progression. Its persistence in CRC liver metastasis tissues raises questions about its role in modulating local and systemic immune responses and influencing recurrence patterns. This retrospective cohort study of 218 patients with CRC liver metastasis investigated the association of F. nucleatum in CRC liver metastasis tissues with systemic inflammation, TIM alterations, and the number of metastatic organs involved in recurrence. Two-step polymerase chain reaction (PCR), including digital PCR, detected F. nucleatum in 42% (92/218) of fresh-frozen specimens of CRC liver metastases. Compared with the F. nucleatum-none group, the F. nucleatum-high group showed higher C-reactive protein levels (0.82 vs. 0.22 mg/dL; Ptrend = 0.02), lower numbers of CD8+ cells (33.2 vs. 65.3 cells/mm2; Ptrend = 0.04) and FOXP3+ cells (11.3 vs. 21.7 cells/mm2; Ptrend = 0.01) in the TIM, and a greater number of metastatic organs involved in recurrence (1.6 vs. 1.1; p < 0.001). The presence of F. nucleatum in CRC liver metastasis tissues was associated with increased systemic inflammation, TIM alterations, and a greater number of metastatic organs involved in recurrence. These findings suggest a potential contribution of F. nucleatum to the metastatic propensity of CRC cells and could inform future research to enhance understanding of the interaction between tumor, host, and microbes in the metastatic process.

在原发性结直肠癌(CRC)中,核分枝杆菌的存在与免疫抑制性肿瘤免疫微环境(TIM)有关,导致肿瘤进展。它在 CRC 肝转移组织中的持续存在使人们对其在调节局部和全身免疫反应以及影响复发模式方面的作用产生了疑问。这项对 218 例 CRC 肝转移患者进行的回顾性队列研究调查了 CRC 肝转移组织中的 F. nucleatum 与全身炎症、TIM 改变和复发涉及的转移器官数量的关系。包括数字 PCR 在内的两步聚合酶链反应(PCR)在 42% (92/218)的 CRC 肝转移灶新鲜冷冻标本中检测到了 F. nucleatum。与无F.nucleatum组相比,F.nucleatum高发组的C反应蛋白水平更高(0.82 vs. 0.22 mg/dL;Ptrend = 0.02),CD8+细胞数量更少(33.2 vs. 65.3 cells/mm2;Ptrend = 0.05),CD8+细胞数量更多。65.3 cells/mm2; Ptrend = 0.04)和 FOXP3+ cells(11.3 vs. 21.7 cells/mm2; Ptrend = 0.01),复发涉及的转移器官数量更多(1.6 vs. 1.1; Ptrend = 0.01)。
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引用次数: 0
Accurate predictors of immune checkpoint inhibitors in patients with gallbladder cancer 胆囊癌患者使用免疫检查点抑制剂的准确预测指标。
IF 4.5 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-14 DOI: 10.1111/cas.16235
Naimei Li, Shuang Deng

Immune checkpoint inhibitors (ICIs) are effective for biliary tract cancers, but data on gallbladder cancer (GBC) are limited. In a recent issue of Cancer Science, Cheng et al.1 aimed to assess the efficacy of ICIs in GBC and explore the clinicopathologic and molecular markers associated with ICI benefits. Based on logistic regression analysis, they found that alcohol intake history, a carcinoembryonic antigen (CEA) level ≥ 100 U/mL, and cutaneous immune-related adverse events (irAEs) were independent prognostic factors for these patients. High carcinoembryonic antigen (CEA) levels, cutaneous irAEs, high CD8+ T-cell infiltration, and an immune inflamed phenotype could be useful for predicting the efficacy of ICIs in GBC patients. However, in this letter, we raise concerns about the statistical method used in this study, while the prognostic factors or predictors for GBC patients may be different.

For a prognostic factors or predictors logistic regression analysis, the basic statistical rule demands 1 covariate per 10 outcome events.2-4 However, the univariable and multivariable Cox proportional hazards regression model in Table 2 of Cheng's study breaks this basic statistical rule. We could observe that there were 21 variables in Table 2 of Cheng's paper that were generated from only 43 PD patients (outcome) who developed tumor recurrence or progressed to death. In other words, analysis of these 21 variables needs at least 210 PD outcome patients, not the 43 PD patients reported in this study. Thus, these overfitted univariable and multivariable logistic models could not produce reliable results, therefore the results in Cheng's study may not be accurate predictors for these patients in the clinic.

To reduce the variables in the predictor logistic regression analysis, the author could compare the outcome group and the non-outcome group. Finding the significant variables between these two groups and using the reduced variables to carry out the predictor logistic regression analysis would lead to more reliable statistical results. Additionally, to finally corroborate Cheng's conclusion, other large sample size results or a validation cohort is needed to validate the predictor results reported in this study.

Last, we congratulate Cheng et al. for their outstanding work despite these comments.

Naimei Li: Writing – original draft. Shuang Deng: Conceptualization; writing – original draft; writing – review and editing.

None.

The authors declare no conflict of interest.

Approval of the research protocol by an Institutional Reviewer Board: N/A.

Informed consent: N/A.

Registry and the Registration No. of the study: N/A.

Animal Studies: N/A.

免疫检查点抑制剂(ICIs)对胆道癌症有效,但有关胆囊癌(GBC)的数据却很有限。在最近一期的《癌症科学》(Cancer Science)杂志上,Cheng 等人1 旨在评估 ICIs 对 GBC 的疗效,并探索与 ICI 受益相关的临床病理和分子标记物。基于逻辑回归分析,他们发现酒精摄入史、癌胚抗原(CEA)水平≥ 100 U/mL和皮肤免疫相关不良事件(irAEs)是这些患者的独立预后因素。高癌胚抗原(CEA)水平、皮肤免疫相关不良事件(irAEs)、高 CD8+ T 细胞浸润和免疫炎症表型可能有助于预测 ICIs 对 GBC 患者的疗效。对于预后因素或预测因素的逻辑回归分析,基本的统计规则是每 10 个结果事件需要 1 个协变量。2-4 然而,Cheng 研究表 2 中的单变量和多变量 Cox 比例危险回归模型打破了这一基本统计规则。我们可以观察到,在 Cheng 的论文表 2 中,有 21 个变量是仅从 43 例出现肿瘤复发或进展至死亡的肺结核患者(结果)中产生的。换句话说,对这 21 个变量进行分析至少需要 210 个 PD 结果患者,而不是本研究中报告的 43 个 PD 患者。因此,这些过度拟合的单变量和多变量逻辑模型无法产生可靠的结果,因此 Cheng 的研究结果可能无法准确预测临床中的这些患者。为了减少预测逻辑回归分析中的变量,作者可以将结果组和非结果组进行比较,找出这两组之间的重要变量,然后使用减少的变量进行预测逻辑回归分析,这样得出的统计结果会更可靠。此外,要最终证实程的结论,还需要其他大样本量的结果或验证队列来验证本研究中报告的预测结果。最后,尽管有这些意见,我们还是要祝贺程等人的杰出工作。邓爽:构思;写作--原稿;写作--审阅和编辑。作者声明无利益冲突:不适用。知情同意:注册表和研究注册号:不适用:动物研究:不适用:动物研究:不适用。
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引用次数: 0
Mechanism research of non-coding RNA in immune checkpoint inhibitors therapy 非编码 RNA 在免疫检查点抑制剂治疗中的机制研究。
IF 4.5 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-13 DOI: 10.1111/cas.16309
Jie Bian, Rui Shao, Juan Li, Jing-Feng Zhu, Ai-Zhong Shao, Chao Liu, L. V. Lu, Hui-Wen Pan, Yi-Jun Shi, Na Fang

Immune checkpoint inhibitor (ICI) therapies for tumors of different systems have attained significant achievements and have changed the current situation of tumor treatment due to their therapeutic characteristics of high specificity and low side effects. The immune checkpoint Programmed death 1/Programmed cell death-Ligand 1 (PD-1/PD-L1) axis exerts a vital role in the immune escape of tumor cells. As a result, it has become a key target for tumor immunotherapy. Therefore, to perfect research into potential regulatory factors for the PD-1/PD-L1 axis, in order to understand and illustrate tumor ICI therapy mechanisms, is a significant goal. Moreover, ncRNA has been verified to regulate the PD-1/PD-L1 axis in the tumor immune microenvironment to regulate tumor genesis and development. ncRNAs can improve or decrease the efficacy of ICI therapy by modulating PD-L1 expression. This review aimed to investigate the mechanisms of action of ncRNA in regulating the PD-1/PD-L1 axis in ICI therapy, to provide more efficient immunotherapy for tumors of different systems.

针对不同系统肿瘤的免疫检查点抑制剂(ICI)疗法取得了重大成果,以其高特异性、低副作用的治疗特点改变了肿瘤治疗的现状。免疫检查点程序性死亡 1/程序性细胞死亡配体 1(PD-1/PD-L1)轴在肿瘤细胞的免疫逃逸中发挥着重要作用。因此,它已成为肿瘤免疫疗法的关键靶点。因此,完善对 PD-1/PD-L1 轴潜在调控因子的研究,以了解和阐明肿瘤 ICI 治疗机制是一个重要目标。此外,ncRNA已被证实可在肿瘤免疫微环境中调控PD-1/PD-L1轴,从而调控肿瘤的发生和发展。本综述旨在研究 ncRNA 在 ICI 治疗中调节 PD-1/PD-L1 轴的作用机制,为不同系统的肿瘤提供更有效的免疫治疗。
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引用次数: 0
Correction to: AC016405.3, a novel long noncoding RNA, acts as a tumor suppressor through modulation of TET2 by microRNA-19a-5p sponging in glioblastoma 更正:新型长非编码 RNA AC016405.3 在胶质母细胞瘤中通过 microRNA-19a-5p sponging 调节 TET2 发挥肿瘤抑制因子的作用。
IF 4.5 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-09 DOI: 10.1111/cas.16277

Siyang Ren, Yinghui Xu. AC016405.3, a novel long noncoding RNA, acts as a tumor suppressor through modulation of TET2 by microRNA-19a-5p sponging in glioblastoma. Cancer Science. 2019;110:1621–1632.

We apologize for this error.

任思阳 徐英辉新型长非编码RNA AC016405.3在胶质母细胞瘤中通过microRNA-19a-5p海绵化调节TET2而发挥抑瘤作用Cancer Science.2019;110:1621-1632.We apologize for this error.
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引用次数: 0
A multicenter study on deep learning for glioblastoma auto-segmentation with prior knowledge in multimodal imaging 利用多模态成像中的先验知识对胶质母细胞瘤自动分割进行深度学习的多中心研究。
IF 4.5 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-09 DOI: 10.1111/cas.16304
Suqing Tian, Yinglong Liu, Xinhui Mao, Xin Xu, Shumeng He, Lecheng Jia, Wei Zhang, Peng Peng, Junjie Wang

A precise radiotherapy plan is crucial to ensure accurate segmentation of glioblastomas (GBMs) for radiation therapy. However, the traditional manual segmentation process is labor-intensive and heavily reliant on the experience of radiation oncologists. In this retrospective study, a novel auto-segmentation method is proposed to address these problems. To assess the method's applicability across diverse scenarios, we conducted its development and evaluation using a cohort of 148 eligible patients drawn from four multicenter datasets and retrospective data collection including noncontrast CT, multisequence MRI scans, and corresponding medical records. All patients were diagnosed with histologically confirmed high-grade glioma (HGG). A deep learning-based method (PKMI-Net) for automatically segmenting gross tumor volume (GTV) and clinical target volumes (CTV1 and CTV2) of GBMs was proposed by leveraging prior knowledge from multimodal imaging. The proposed PKMI-Net demonstrated high accuracy in segmenting, respectively, GTV, CTV1, and CTV2 in an 11-patient test set, achieving Dice similarity coefficients (DSC) of 0.94, 0.95, and 0.92; 95% Hausdorff distances (HD95) of 2.07, 1.18, and 3.95 mm; average surface distances (ASD) of 0.69, 0.39, and 1.17 mm; and relative volume differences (RVD) of 5.50%, 9.68%, and 3.97%. Moreover, the vast majority of GTV, CTV1, and CTV2 produced by PKMI-Net are clinically acceptable and require no revision for clinical practice. In our multicenter evaluation, the PKMI-Net exhibited consistent and robust generalizability across the various datasets, demonstrating its effectiveness in automatically segmenting GBMs. The proposed method using prior knowledge in multimodal imaging can improve the contouring accuracy of GBMs, which holds the potential to improve the quality and efficiency of GBMs' radiotherapy.

精确的放射治疗计划对于确保准确分割胶质母细胞瘤(GBM)以进行放射治疗至关重要。然而,传统的人工分割过程耗费大量人力,而且严重依赖放射肿瘤专家的经验。在这项回顾性研究中,提出了一种新型自动分割方法来解决这些问题。为了评估该方法在不同情况下的适用性,我们从四个多中心数据集和回顾性数据收集(包括非对比 CT、多序列 MRI 扫描和相应的医疗记录)中抽取了 148 名符合条件的患者,对其进行了开发和评估。所有患者均经组织学确诊为高级别胶质瘤(HGG)。通过利用多模态成像的先验知识,提出了一种基于深度学习的方法(PKMI-Net),用于自动分割GBM的肿瘤总体积(GTV)和临床目标体积(CTV1和CTV2)。所提出的 PKMI-Net 在 11 名患者的测试集中分别对 GTV、CTV1 和 CTV2 进行了高精度分割,Dice 相似系数 (DSC) 分别达到 0.94、0.95 和 0.92;95% Hausdorff 距离 (HD95) 分别为 2.07、1.18 和 3.95 毫米;平均表面距离 (ASD) 分别为 0.69、0.39 和 1.17 毫米;相对体积差异 (RVD) 分别为 5.50%、9.68% 和 3.97%。此外,PKMI-Net 生成的绝大多数 GTV、CTV1 和 CTV2 在临床上都是可以接受的,无需在临床实践中进行修改。在我们的多中心评估中,PKMI-Net 在各种数据集上都表现出了一致而强大的通用性,证明了它在自动分割 GBM 方面的有效性。利用多模态成像中的先验知识提出的方法可以提高 GBM 的轮廓准确性,从而有望提高 GBM 放疗的质量和效率。
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引用次数: 0
CLG promotes mTOR/ULK1 pathway-mediated autophagy to inhibit OS development by inhibiting TRAF6-mediated FLT3 ubiquitination CLG通过抑制TRAF6介导的FLT3泛素化,促进mTOR/ULK1通路介导的自噬,从而抑制OS的发展。
IF 4.5 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-09 DOI: 10.1111/cas.16274
Xiongjie Huang, Yanran Huang, Bin Peng, Junfang Wang, Huiyu Tang, Yanming Chen

Corilagin (CLG) has antitumor activities in certain human malignant cancers. Herein, the effects and mechanisms of CLG on osteosarcoma (OS) were investigated. OS cell viability and proliferation were detected by MTT and colony formation assay. Cell cycle and apoptosis were examined using flow cytometry. The interaction between TRAF6 and FLT3 was investigated using a co-immunoprecipitation assay. Results demonstrated that CLG treatment inhibited OS cell viability and proliferation but promoted OS cell autophagy and apoptosis in a concentration-dependent manner. Mechanically, CLG inhibited TRAF6-mediated FLT3 ubiquitination degradation. TRAF6 overexpression abolished the effects of CLG on OS cell proliferation, autophagy, and apoptosis. Finally, CLG administration inhibited OS tumor growth in mice by inducing autophagy-dependent apoptosis. Taken together, CLG inhibited OS progression by facilitating mTOR/ULK1 pathway-mediated autophagy through inhibiting TRAF6-mediated FLT3 ubiquitination, which indicated that CLG was a promising candidate for the treatment of OS.

柯里拉京(CLG)对某些人类恶性癌症具有抗肿瘤活性。本文研究了CLG对骨肉瘤(OS)的作用和机制。通过 MTT 和集落形成试验检测了骨肉瘤细胞的活力和增殖。流式细胞术检测了细胞周期和细胞凋亡。使用共免疫共沉淀试验研究了 TRAF6 和 FLT3 之间的相互作用。结果表明,CLG以浓度依赖的方式抑制了OS细胞的活力和增殖,但促进了OS细胞的自噬和凋亡。CLG从机制上抑制了TRAF6介导的FLT3泛素化降解。TRAF6过表达可消除CLG对OS细胞增殖、自噬和凋亡的影响。最后,CLG通过诱导自噬依赖性凋亡抑制了小鼠OS肿瘤的生长。综上所述,CLG通过抑制TRAF6介导的FLT3泛素化来促进mTOR/ULK1通路介导的自噬,从而抑制了OS的进展,这表明CLG是一种治疗OS的有希望的候选药物。
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引用次数: 0
Overcoming immunotherapy resistance and inducing abscopal effects with boron neutron immunotherapy (B-NIT) 利用硼中子免疫疗法(B-NIT)克服免疫疗法的抗药性并诱导脱落效应。
IF 4.5 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-09 DOI: 10.1111/cas.16298
Takuya Fujimoto, Osamu Yamasaki, Noriyuki Kanehira, Hirokazu Matsushita, Yoshinori Sakurai, Naoya Kenmotsu, Ryo Mizuta, Natsuko Kondo, Takushi Takata, Mizuki Kitamatsu, Kazuyo Igawa, Atsushi Fujimura, Yoshihiro Otani, Makoto Shirakawa, Kunitoshi Shigeyasu, Fuminori Teraishi, Yosuke Togashi, Minoru Suzuki, Toshiyoshi Fujiwara, Hiroyuki Michiue

Immune checkpoint inhibitors (ICIs) are effective against many advanced malignancies. However, many patients are nonresponders to immunotherapy, and overcoming this resistance to treatment is important. Boron neutron capture therapy (BNCT) is a local chemoradiation therapy with the combination of boron drugs that accumulate selectively in cancer and the neutron irradiation of the cancer site. Here, we report the first boron neutron immunotherapy (B-NIT), combining BNCT and ICI immunotherapy, which was performed on a radioresistant and immunotherapy-resistant advanced-stage B16F10 melanoma mouse model. The BNCT group showed localized tumor suppression, but the anti-PD-1 antibody immunotherapy group did not show tumor suppression. Only the B-NIT group showed strong tumor growth inhibition at both BNCT-treated and shielded distant sites. Intratumoral CD8+ T-cell infiltration and serum high mobility group box 1 (HMGB1) levels were higher in the B-NIT group. Analysis of CD8+ T cells in tumor-infiltrating lymphocytes (TILs) showed that CD62L- CD44+ effector memory T cells and CD69+ early-activated T cells were predominantly increased in the B-NIT group. Administration of CD8-depleting mAb to the B-NIT group completely suppressed the augmented therapeutic effects. This indicated that B-NIT has a potent immune-induced abscopal effect, directly destroying tumors with BNCT, inducing antigen-spreading effects, and protecting normal tissue. B-NIT, immunotherapy combined with BNCT, is the first treatment to overcome immunotherapy resistance in malignant melanoma. In the future, as its therapeutic efficacy is demonstrated not only in melanoma but also in other immunotherapy-resistant malignancies, B-NIT can become a new treatment candidate for advanced-stage cancers.

免疫检查点抑制剂(ICIs)对许多晚期恶性肿瘤有效。然而,许多患者对免疫疗法没有反应,克服这种耐药性非常重要。硼中子俘获疗法(BNCT)是一种局部化学放疗,它结合了选择性蓄积在癌症中的硼药物和对癌症部位的中子照射。在此,我们首次报道了硼中子免疫疗法(B-NIT),该疗法结合了 BNCT 和 ICI 免疫疗法,在放射抗性和免疫疗法抗性的晚期 B16F10 黑色素瘤小鼠模型上实施。BNCT组显示出局部肿瘤抑制,但抗PD-1抗体免疫疗法组未显示出肿瘤抑制。只有B-NIT组在BNCT处理过的部位和屏蔽的远处部位都表现出了很强的肿瘤生长抑制作用。B-NIT组的瘤内CD8+ T细胞浸润和血清高迁移率基团框1(HMGB1)水平较高。对肿瘤浸润淋巴细胞(TILs)中CD8+ T细胞的分析表明,B-NIT组的CD62L- CD44+效应记忆T细胞和CD69+早活化T细胞主要有所增加。给 B-NIT 组注射 CD8 清除 mAb 可完全抑制增强的治疗效果。这表明,B-NIT 具有强大的免疫诱导脱落效应,能直接用 BNCT 破坏肿瘤,诱导抗原扩散效应,并保护正常组织。B-NIT是结合BNCT的免疫疗法,是首个克服恶性黑色素瘤免疫疗法耐药性的疗法。未来,随着其疗效不仅在黑色素瘤中得到证实,而且在其他免疫治疗耐药的恶性肿瘤中也得到证实,B-NIT 将成为晚期癌症的一种新的候选治疗方法。
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引用次数: 0
Newly developed humanized anti-CKAP4 antibody suppresses pancreatic cancer growth by inhibiting DKK1-CKAP4 signaling 新开发的人源化抗 CKAP4 抗体通过抑制 DKK1-CKAP4 信号传导抑制胰腺癌生长。
IF 4.5 2区 医学 Q1 ONCOLOGY Pub Date : 2024-08-08 DOI: 10.1111/cas.16278
Ryota Sada, Hideki Yamamoto, Shinji Matsumoto, Akikazu Harada, Akira Kikuchi

Cytoskeleton-associated protein 4 (CKAP4) is a cell surface receptor for Dickkopf 1 (DKK1), a secreted protein. The DKK1–CKAP4 pathway is activated in various malignant tumors, including pancreatic, lung, esophageal, and liver cancers, to promote tumor growth. Thus, CKAP4 has been expected to represent a novel molecular target of cancer therapy. Recombinant mouse anti-CKAP4 antibodies were generated based on an original mouse antibody (3F11-2B10) and inhibited DKK1–CKAP4 signaling and xenograft tumor formation induced by pancreatic cancer cells, which was comparable with 3F11-2B10. From the 3F11-2B10 nucleotide sequence, humanized anti-CKAP4 antibody (Hv1Lt1) was subsequently developed. The binding affinity of Hv1Lt1 for CKAP4 was superior to that of 3F11-2B10. Hv1Lt1 inhibited DKK1 binding to CKAP4, AKT activity, and sphere formation of pancreatic cancer cells, which was comparable with 3F11-2B10. Hv1Lt1 also suppressed xenograft tumor formation induced by human pancreatic cancer cells and tumor growth in murine cancer models, in which murine pancreatic cancer organoids were orthotopically transplanted into the pancreas. In resected tumor samples from mice treated with Hv1Lt1, anti-tumor immune reactions were modulated and cytotoxic T cells were highly infiltrated in the tumor microenvironment. Additionally, combination of Hv1Lt1 and other chemotherapy drugs exhibited stronger effects compared with monotherapy. These results suggest that Hv1Lt1 represents a promising anti-cancer therapy.

细胞骨架相关蛋白 4(CKAP4)是分泌蛋白 Dickkopf 1(DKK1)的细胞表面受体。在各种恶性肿瘤(包括胰腺癌、肺癌、食管癌和肝癌)中,DKK1-CKAP4 通路被激活,从而促进肿瘤生长。因此,CKAP4有望成为癌症治疗的新分子靶点。在一种原始小鼠抗体(3F11-2B10)的基础上产生了重组小鼠抗 CKAP4 抗体,该抗体能抑制 DKK1-CKAP4 信号传导和胰腺癌细胞诱导的异种移植肿瘤的形成,其效果与 3F11-2B10 相当。根据 3F11-2B10 的核苷酸序列,随后开发出了人源化的抗 CKAP4 抗体(Hv1Lt1)。Hv1Lt1 与 CKAP4 的结合亲和力优于 3F11-2B10。Hv1Lt1 可抑制 DKK1 与 CKAP4 的结合、AKT 活性和胰腺癌细胞球的形成,其效果与 3F11-2B10 相当。Hv1Lt1 还能抑制人胰腺癌细胞诱导的异种移植肿瘤的形成,以及小鼠癌症模型中肿瘤的生长。在用 Hv1Lt1 治疗的小鼠切除肿瘤样本中,抗肿瘤免疫反应得到调节,细胞毒性 T 细胞高度浸润肿瘤微环境。此外,与单药治疗相比,Hv1Lt1 与其他化疗药物联合使用的效果更强。这些结果表明,Hv1Lt1 是一种很有前景的抗癌疗法。
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Cancer Science
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