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A Prostatic Intraepithelial Neoplasia-Dependent p27Kip1 Checkpoint Induces Senescence and Inhibits Cell Proliferation and Cancer Progression. 前列腺上皮内瘤依赖 p27Kip1 检查点诱导衰老并抑制细胞增殖和癌症进展
IF 48.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-06-10 Epub Date: 2024-05-30 DOI: 10.1016/j.ccell.2024.05.008
Pradip K Majumder, Chiara Grisanzio, Fionnuala O'Connell, Marc Barry, Joseph M Brito, Qing Xu, Isil Guney, Raanan Berger, Paula Herman, Rachel Bikoff, Giuseppe Fedele, Won-Ki Baek, Shunyou Wang, Katharine Ellwood-Yen, Hong Wu, Charles L Sawyers, Sabina Signoretti, William C Hahn, Massimo Loda, William R Sellers
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引用次数: 0
Finding the sweet spot: Targeting RAS in tumors while sparing normal tissue 寻找甜蜜点:靶向肿瘤中的 RAS,同时保护正常组织
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-06-10 DOI: 10.1016/j.ccell.2024.05.020
Naiara Perurena, Karen Cichowski

The development of mutant-selective KRAS inhibitors represents a major therapeutic advance; however, patients can develop resistance through feedback mechanisms and genetic alterations in the RAS pathway. Three publications in Nature and Cancer Discovery describe a promising RAS(ON) multi-selective inhibitor that simultaneously targets oncogenic RAS and multiple potential resistance mechanisms while sparing normal tissue.

突变选择性 KRAS 抑制剂的开发是治疗上的一大进步;然而,患者可能会通过 RAS 通路中的反馈机制和基因改变产生耐药性。自然》(Nature)和《癌症发现》(Cancer Discovery)杂志上发表的三篇论文介绍了一种很有前景的 RAS(ON) 多选择抑制剂,它能同时针对致癌 RAS 和多种潜在的耐药机制,同时保护正常组织。
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引用次数: 0
Mapping myeloid cell function: Spatial diversity in tumor and neuronal microenvironment 绘制髓系细胞功能图:肿瘤和神经元微环境的空间多样性
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-06-10 DOI: 10.1016/j.ccell.2024.05.018
Giulia Villa, Daniel Delev, Dieter Henrik Heiland

In this issue of Cancer Cell, Zhong et al. explore the dual role of TREM2 in glioblastoma-associated myeloid cells, demonstrating its function in promoting inflammation at the tumor-neural interface and suppression within the tumor core, influenced by the local microenvironment. These findings open up promising prospects for advancements in neuro-oncological immunotherapy.

在本期《癌细胞》(Cancer Cell)杂志上,Zhong 等人探讨了 TREM2 在胶质母细胞瘤相关髓系细胞中的双重作用,证明了它在肿瘤-神经界面促进炎症和在肿瘤核心内受局部微环境影响抑制炎症的功能。这些发现为神经肿瘤免疫疗法的发展开辟了广阔的前景。
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引用次数: 0
The temporal progression of lung immune remodeling during breast cancer metastasis. 乳腺癌转移过程中肺部免疫重塑的时间进程
IF 48.8 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-06-10 Epub Date: 2024-05-30 DOI: 10.1016/j.ccell.2024.05.004
Christopher S McGinnis, Zhuang Miao, Daphne Superville, Winnie Yao, Andrei Goga, Nathan E Reticker-Flynn, Juliane Winkler, Ansuman T Satpathy

Tumor metastasis requires systemic remodeling of distant organ microenvironments that impacts immune cell phenotypes, population structure, and intercellular communication. However, our understanding of immune phenotypic dynamics in the metastatic niche remains incomplete. Here, we longitudinally assayed lung immune transcriptional profiles in the polyomavirus middle T antigen (PyMT) and 4T1 metastatic breast cancer models from primary tumorigenesis, through pre-metastatic niche formation, to the final stages of metastatic outgrowth at single-cell resolution. Computational analyses of these data revealed a TLR-NFκB inflammatory program enacted by both peripherally derived and tissue-resident myeloid cells that correlated with pre-metastatic niche formation and mirrored CD14+ "activated" myeloid cells in the primary tumor. Moreover, we observed that primary tumor and metastatic niche natural killer (NK) cells are differentially regulated in mice and human patient samples, with the metastatic niche featuring elevated cytotoxic NK cell proportions. Finally, we identified cell-type-specific dynamic regulation of IGF1 and CCL6 signaling during metastatic progression that represents anti-metastatic immunotherapy candidate pathways.

肿瘤转移需要对远处器官微环境进行系统重塑,从而影响免疫细胞表型、群体结构和细胞间通讯。然而,我们对转移龛中免疫表型动态的了解仍不全面。在这里,我们以单细胞分辨率纵向检测了多瘤病毒中间T抗原(PyMT)和4T1转移性乳腺癌模型中的肺部免疫转录谱,从原发性肿瘤发生、转移前生态位形成到转移生长的最后阶段。对这些数据的计算分析表明,外周衍生的和组织驻留的髓样细胞制定了TLR-NFκB炎症程序,该程序与转移前的龛形成相关,并反映了原发肿瘤中CD14+"活化 "的髓样细胞。此外,我们还观察到,在小鼠和人类患者样本中,原发肿瘤和转移龛中的自然杀伤(NK)细胞受到不同程度的调控,转移龛中的细胞毒性 NK 细胞比例升高。最后,我们发现了转移进展过程中细胞类型特异性的 IGF1 和 CCL6 信号动态调控,这代表了抗转移免疫疗法的候选途径。
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引用次数: 0
T-Lymphoblastic Lymphoma Cells Express High Levels of BCL2, S1P1, and ICAM1, Leading to a Blockade of Tumor Cell Intravasation T 淋巴细胞淋巴瘤细胞表达高水平的 BCL2、S1P1 和 ICAM1,导致肿瘤细胞内侵受阻
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-06-10 DOI: 10.1016/j.ccell.2024.05.019
Hui Feng, David L. Stachura, Richard M. White, Alejandro Gutierrez, Lu Zhang, Takaomi Sanda, Cicely A. Jette, Joseph R. Testa, Donna S. Neuberg, David M. Langenau, Jeffery L. Kutok, Leonard I. Zon, David Traver, Mark D. Fleming, John P. Kanki, A. Thomas Look
No Abstract
无摘要
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引用次数: 0
Hand in hand to successful immunotherapy: CD8+ T cells and M1-like macrophages swap the baton 牵手成功的免疫疗法:CD8+ T 细胞和 M1 样巨噬细胞互换指挥棒
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-06-10 DOI: 10.1016/j.ccell.2024.05.012
Abir Hussein, Slava Stamova, Maria Xydia, Philipp Beckhove

Cancer immunotherapy is a pillar of clinical oncology but only achieves long-term remissions in a minority of cases. In this issue, van Elsas et al. show that effective immunotherapy requires a series of processes orchestrated by CD8+ T cells that result in the recruitment and local activation of M1-like macrophages.

癌症免疫疗法是临床肿瘤学的支柱,但只有少数病例能实现长期缓解。在本期杂志中,van Elsas 等人的研究表明,有效的免疫疗法需要一系列由 CD8+ T 细胞协调的过程,这些过程会导致 M1 样巨噬细胞的招募和局部激活。
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引用次数: 0
Interruption of the intratumor CD8+ T cell:Treg crosstalk improves the efficacy of PD-1 immunotherapy 阻断肿瘤内CD8+ T细胞:Treg串扰可提高PD-1免疫疗法的疗效
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-06-10 DOI: 10.1016/j.ccell.2024.05.013
Shannon N. Geels, Alexander Moshensky, Rachel S. Sousa, Claire Murat, Matias A. Bustos, Benjamin L. Walker, Rima Singh, Stacey N. Harbour, Giselle Gutierrez, Michael Hwang, Thorsten R. Mempel, Casey T. Weaver, Qing Nie, Dave S.B. Hoon, Anand K. Ganesan, Shivashankar Othy, Francesco Marangoni

PD-1 blockade unleashes potent antitumor activity in CD8+ T cells but can also promote immunosuppressive T regulatory (Treg) cells, which may worsen the response to immunotherapy. Tumor-Treg inhibition is a promising strategy to improve the efficacy of checkpoint blockade immunotherapy; however, our understanding of the mechanisms supporting tumor-Tregs during PD-1 immunotherapy is incomplete. Here, we show that PD-1 blockade increases tumor-Tregs in mouse models of melanoma and metastatic melanoma patients. Mechanistically, Treg accumulation is not caused by Treg-intrinsic inhibition of PD-1 signaling but depends on an indirect effect of activated CD8+ T cells. CD8+ T cells produce IL-2 and colocalize with Tregs in mouse and human melanomas. IL-2 upregulates the anti-apoptotic protein ICOS on tumor-Tregs, promoting their accumulation. Inhibition of ICOS signaling before PD-1 immunotherapy improves control over immunogenic melanoma. Thus, interrupting the intratumor CD8+ T cell:Treg crosstalk represents a strategy to enhance the therapeutic efficacy of PD-1 immunotherapy.

PD-1阻断可释放CD8+ T细胞的强大抗肿瘤活性,但也会促进免疫抑制性T调节(Treg)细胞,从而可能会恶化对免疫疗法的反应。抑制肿瘤-Treg是提高检查点阻断免疫疗法疗效的一种很有前景的策略;然而,我们对PD-1免疫疗法期间支持肿瘤-Treg的机制的了解还不全面。在这里,我们发现在黑色素瘤小鼠模型和转移性黑色素瘤患者中,PD-1阻断会增加肿瘤-Tregs。从机理上讲,Treg 的积累并不是由 PD-1 信号的 Treg 内在抑制引起的,而是取决于活化的 CD8+ T 细胞的间接作用。CD8+ T细胞产生IL-2,并与小鼠和人类黑色素瘤中的Tregs共定位。IL-2 上调肿瘤-Tregs 上的抗凋亡蛋白 ICOS,促进它们的聚集。在PD-1免疫疗法之前抑制ICOS信号传导可改善对免疫原性黑色素瘤的控制。因此,阻断肿瘤内CD8+ T细胞与Treg的串扰是提高PD-1免疫疗法疗效的一种策略。
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引用次数: 0
Integrated single cell analysis reveals co-evolution of malignant B cells and tumor micro-environment in transformed follicular lymphoma 综合单细胞分析揭示了转化型滤泡淋巴瘤中恶性 B 细胞和肿瘤微环境的共同进化过程
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-06-10 DOI: 10.1016/j.ccell.2024.05.011
Clémentine Sarkozy, Shaocheng Wu, Katsuyoshi Takata, Tomohiro Aoki, Susana B. Neriah, Katy Milne, Talia Goodyear, Celia Strong, Tashi Rastogi, Laura K. Hilton, Daniel Lai, Laurie H. Sehn, Pedro Farinha, Brad H. Nelson, Andrew Weng, Marco Marra, David W. Scott, Jeffrey W. Craig, Christian Steidl, Andrew Roth

Histological transformation of follicular lymphoma (FL) to aggressive forms is associated with poor outcome. Phenotypic consequences of this evolution and its impact on the tumor microenvironment (TME) remain unknown. We perform single-cell whole genome sequencing (scWGS) and transcriptome sequencing (scWTS) of 11 paired pre/post-transformation patient samples and scWTS of additional samples from patients without transformation. Our analysis reveals evolutionary dynamics of transformation at single-cell resolution, highlighting a shifting TME landscape, with an emerging immune-cell exhaustion signature, co-evolving with the shifting malignant B phenotype in a regulatory ecosystem. Integration of scWGS and scWTS identifies malignant cell pathways upregulated during clonal tumor evolution. Using multi-color immunofluorescence, we transfer these findings to a TME-based transformation biomarker, subsequently validated in two independent pretreatment cohorts. Taken together, our results provide a comprehensive view of the combined genomic and phenotypic evolution of malignant cells during transformation and shifting crosstalk between malignant cells and the TME.

滤泡性淋巴瘤(FL)在组织学上转变为侵袭性淋巴瘤与预后不良有关。这种演变的表型后果及其对肿瘤微环境(TME)的影响仍然未知。我们对 11 例转化前后配对的患者样本进行了单细胞全基因组测序(scWGS)和转录组测序(scWTS),并对未转化患者的其他样本进行了单细胞全基因组测序(scWGS)和转录组测序(scWTS)。我们的分析揭示了转化在单细胞分辨率上的进化动态,凸显了不断变化的TME景观,其中有一个新出现的免疫细胞衰竭特征,在一个调控生态系统中与不断变化的恶性B表型共同进化。整合 scWGS 和 scWTS 可识别克隆性肿瘤演变过程中上调的恶性细胞通路。利用多色免疫荧光,我们将这些发现转化为基于 TME 的转化生物标记物,随后在两个独立的预处理队列中进行了验证。总之,我们的研究结果提供了一个全面的视角,让人们了解恶性细胞在转化过程中基因组和表型的综合演变,以及恶性细胞与 TME 之间的串扰变化。
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引用次数: 0
Testing dilemmas in the clinic: Lessons learned from biomarker-based drug development 临床试验困境:从基于生物标记的药物开发中汲取的经验教训
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-06-10 DOI: 10.1016/j.ccell.2024.05.014
Sahar Barjesteh van Waalwijk van Doorn-Khosrovani, Olga Kholmanskikh Van Criekingen, Simone Koole, David M. Thomas, Hans Gelderblom

Various tests based on different biomarkers have been developed to identify the best candidates for poly(ADP-ribose) polymerase (PARP)-inhibitor therapy. However, due to the absence of harmonization regarding these complex biomarkers, along with various cutoff points and unknown spatial and temporal variations, it is difficult to define the clinical utility of each test and ensure uniformity in treatment decision-making. Here, we propose measures to align biomarker definitions and minimum analytical performance characteristics for diagnostics to ensure equitable and sustainable access to precision medicine.

目前已开发出基于不同生物标志物的各种检测方法,以确定接受聚(ADP-核糖)聚合酶(PARP)抑制剂治疗的最佳候选者。然而,由于这些复杂的生物标志物缺乏统一性,再加上不同的截断点和未知的时空变化,很难确定每种检测方法的临床效用并确保治疗决策的统一性。在此,我们提出了统一生物标志物定义和诊断的最低分析性能特征的措施,以确保公平、可持续地获得精准医疗。
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引用次数: 0
Let it be: Preserving tumor-draining lymph nodes in the era of immuno-oncology 顺其自然:在免疫肿瘤学时代保留肿瘤引流淋巴结
IF 50.3 1区 医学 Q1 CELL BIOLOGY Pub Date : 2024-06-10 DOI: 10.1016/j.ccell.2024.05.015
Robert Saddawi-Konefka, Shiruyeh Schokrpur, J. Silvio Gutkind

Solid cancers often progress via metastasis to lymph nodes. Consequently, lymphadenectomy is central to stage cancers and eradicates disease spread. However, mounting evidence suggests that cancer immunotherapies drive antitumor immune responses within lymph nodes. This implies that immunotherapy, delivered with standard oncologic therapies, may require specific treatment sequencing to initiate immunosurveillance and affect primary tumor responses. As supported by recent preclinical and clinical studies, lymphatic-preserving strategies may offer the best promise for driving the next generation of breakthrough immunotherapy approaches.

实体瘤通常通过淋巴结转移发展。因此,淋巴结切除术是癌症分期和根除疾病扩散的关键。然而,越来越多的证据表明,癌症免疫疗法会在淋巴结内产生抗肿瘤免疫反应。这意味着,与标准肿瘤疗法同时进行的免疫疗法可能需要特定的治疗顺序,以启动免疫监视并影响原发性肿瘤反应。最近的临床前和临床研究表明,淋巴保留策略最有希望推动下一代突破性免疫疗法的发展。
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引用次数: 0
期刊
Cancer Cell
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