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Cancer Core Europe: Leveraging Institutional Synergies to Advance Oncology Research and Care Globally. 欧洲癌症核心:利用机构协同作用推动全球肿瘤学研究和护理。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1158/2159-8290.CD-24-0377
Javier Carmona, Elena Chavarria, Kate Donoghue, Christina von Gertten, Petra Oberrauch, Emma Pailler, Giovanni Scoazec, Ruud Weijer, Judith Balmaña, Irene Brana, Cinzia Brunelli, Suzette Delaloge, Marc Deloger, Pierre Delpy, Ingemar Ernberg, Rebecca C Fitzgerald, Elena Garralda, Martin Lablans, Janne Lëhtio, Carlos Lopez, Maialen Fernández, Rosalba Miceli, Paolo Nuciforo, Raquel Perez-Lopez, Elena Provenzano, Marjanka K Schmidt, Cesar Serrano, Neeltje Steeghs, David Tamborero, Valtteri Wirta, Richard D Baird, Karen Barker, Fabrice Barlesi, Michael Baumann, Jonas Bergh, Filippo de Braud, Karim Fizazi, Stefan Fröhling, Alejandro Piris-Giménez, Kenneth Seamon, Michiel S Van der Heijden, Wilbert Zwart, Josep Tabernero

Cancer Core Europe brings together the expertise, resources, and interests of seven leading cancer institutes committed to leveraging collective innovation and collaboration in precision oncology. Through targeted efforts addressing key medical challenges in cancer and partnerships with multiple stakeholders, the consortium seeks to advance cancer research and enhance equitable patient care.

欧洲癌症核心组织汇集了七家领先癌症研究机构的专业知识、资源和兴趣,致力于在精准肿瘤学领域进行集体创新和合作。通过有针对性地应对癌症领域的关键医学挑战,并与多个利益相关方建立合作伙伴关系,该联盟力求推进癌症研究,加强对患者的公平护理。
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引用次数: 0
Combining TIGIT Blockade with MDSC Inhibition Hinders Breast Cancer Bone Metastasis by Activating Antitumor Immunity. 将TIGIT阻断与MDSC抑制相结合,通过激活抗肿瘤免疫力来阻止乳腺癌骨转移。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1158/2159-8290.CD-23-0762
Lea Monteran, Nour Ershaid, Ye'ela Scharff, Yazeed Zoabi, Tamer Sanalla, Yunfeng Ding, Anna Pavlovsky, Yael Zait, Marva Langer, Tal Caller, Anat Eldar-Boock, Camila Avivi, Amir Sonnenblick, Ronit Satchi-Fainaro, Iris Barshack, Noam Shomron, Xiang H-F Zhang, Neta Erez

Bone is the most common site of breast cancer metastasis. Bone metastasis is incurable and is associated with severe morbidity. Utilizing an immunocompetent mouse model of spontaneous breast cancer bone metastasis, we profiled the immune transcriptome of bone metastatic lesions and peripheral bone marrow at distinct metastatic stages, revealing dynamic changes during the metastatic process. We show that cross-talk between granulocytes and T cells is central to shaping an immunosuppressive microenvironment. Specifically, we identified the PD-1 and TIGIT signaling axes and the proinflammatory cytokine IL1β as central players in the interactions between granulocytes and T cells. Targeting these pathways in vivo resulted in attenuated bone metastasis and improved survival, by reactivating antitumor immunity. Analysis of patient samples revealed that TIGIT and IL1β are prominent in human bone metastasis. Our findings suggest that cotargeting immunosuppressive granulocytes and dysfunctional T cells may be a promising novel therapeutic strategy to inhibit bone metastasis. Significance: Temporal transcriptome profiling of the immune microenvironment in breast cancer bone metastasis revealed key communication pathways between dysfunctional T cells and myeloid derived suppressor cells. Cotargeting of TIGIT and IL1β inhibited bone metastasis and improved survival. Validation in patient data implicated these targets as a novel promising approach to treat human bone metastasis.

骨是乳腺癌最常见的转移部位。骨转移是无法治愈的,而且与严重的发病率有关。我们利用免疫功能正常的自发性乳腺癌骨转移小鼠模型,分析了骨转移病灶和外周骨髓在不同转移阶段的免疫转录组,揭示了转移过程中的动态变化。我们发现,粒细胞和 T 细胞之间的串扰是形成免疫抑制微环境的核心。具体来说,我们发现 PD-1 和 TIGIT 信号轴以及促炎细胞因子 IL1b 是粒细胞和 T 细胞之间相互作用的核心角色。在体内靶向这些通路可重新激活抗肿瘤免疫,从而减少骨转移并提高生存率。对患者样本的分析表明,TIGIT和IL1b在人类骨转移中表现突出。我们的研究结果表明,联合靶向免疫抑制性粒细胞和功能失调的T细胞可能是一种很有前景的抑制骨转移的新型治疗策略。
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引用次数: 0
Expression of Concern: Exploiting Drug Addiction Mechanisms to Select against MAPKi-Resistant Melanoma. 表达关切:利用药物成瘾机制选择抗 MAPKi-Resistant 黑色素瘤。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1158/2159-8290.CD-24-0612
Aayoung Hong, Gatien Moriceau, Lu Sun, Shirley Lomeli, Marco Piva, Robert Damoiseaux, Sheri L Holmen, Norman E Sharpless, Willy Hugo, Roger S Lo
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引用次数: 0
Pan-RAF:MEK Molecular Glues Take Center Stage. 泛 RAF:MEK 分子胶占据中心位置。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1158/2159-8290.CD-24-0539
Matthew J Hangauer, Jorge Silvio Gutkind, Fleur M Ferguson

In this issue, Ryan and colleagues describe the preclinical development of a pan-RAF:MEK molecular glue with superior efficacy, brain penetrance, and tolerability in xenograft models of Ras/Raf/MAPK pathway-driven tumors. See related article by Ryan et al., p. 1190 (1).

在本期杂志中,Ryan 及其同事介绍了泛 RAF:MEK 分子胶的临床前开发情况,该分子胶在 Ras/Raf/MAPK 通路驱动的肿瘤异种移植模型中具有卓越的疗效、脑穿透性和耐受性。请参见 Ryan 等人的相关文章,第 1190 页(1)。
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引用次数: 0
Precision Targeting of the Gut Microbiome for Cancer Immunotherapy. 精准靶向肠道微生物组,促进癌症免疫疗法。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1158/2159-8290.CD-24-0538
Pasquale Lombardi, David J Pinato

Transforming gut microbial status from a prognostic trait to a therapeutic target is a key goal to understand and reverse resistance to anticancer immunotherapy. Glitza and colleagues propose selective manipulation of the gut microbiome with SER401 following antibiotic preconditioning and highlight multiple challenges in delivering microbiome manipulation to the clinic. See related article by Glitza et al., p. 1161 (8).

将肠道微生物状态从预后特征转变为治疗靶点是了解和逆转抗癌免疫疗法耐药性的关键目标。Glitza 及其同事建议在抗生素预处理后用 SER401 选择性地操纵肠道微生物组,并强调了将微生物组操纵应用于临床的多重挑战。请参阅 Glitza 等人的相关文章,第 1161 页(8)。
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引用次数: 0
Senescence Defines a Distinct Subset of Myofibroblasts That Orchestrates Immunosuppression in Pancreatic Cancer. 衰老定义了胰腺癌中协调免疫抑制的肌成纤维细胞的独特亚群。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1158/2159-8290.CD-23-0428
Jad I Belle, Devashish Sen, John M Baer, Xiuting Liu, Varintra E Lander, Jiayu Ye, Blake E Sells, Brett L Knolhoff, Ahmad Faiz, Liang-I Kang, Guhan Qian, Ryan C Fields, Li Ding, Hyun Kim, Paolo P Provenzano, Sheila A Stewart, David G DeNardo

Pancreatic ductal adenocarcinoma (PDAC) therapeutic resistance is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer-associated fibroblasts (CAF). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAF) in mouse and human PDAC. These SenCAFs are a phenotypically distinct subset of myofibroblastic CAFs that localize near tumor ducts and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we used an LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Depletion of senescent stromal cells in genetic and pharmacologic PDAC models relieved immune suppression by macrophages, delayed tumor progression, and increased responsiveness to chemotherapy. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction. Significance: CAF heterogeneity in PDAC remains poorly understood. In this study, we identify a novel subpopulation of senescent CAFs that promotes PDAC progression and immunosuppression. Targeting CAF senescence in combination therapies could increase tumor vulnerability to chemo or immunotherapy. See related article by Ye et al., p. 1302.

PDAC 的耐药性在很大程度上归因于其独特的肿瘤微环境,其中蕴含着大量的癌症相关成纤维细胞(CAFs)。最近发现了不同的 CAF 群体,但 CAF 异质性的表型驱动因素和具体影响仍不清楚。在这项研究中,我们发现了小鼠和人类 PDAC 中的衰老肌成纤维细胞 CAFs(SenCAFs)亚群。这些SenCAFs是表型独特的肌成纤维细胞CAFs亚群,它们定位于肿瘤导管附近,并随着PDAC的进展而聚集。为了评估内源性SenCAFs在PDAC中的影响,我们采用了LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC(KPPC-IA)小鼠自发性PDAC模型,并诱导衰老细胞耗竭。在遗传和药物 PDAC 模型中消耗衰老基质细胞可缓解巨噬细胞的免疫抑制、延缓肿瘤进展并提高对化疗的反应性。总之,我们的研究结果表明,SenCAFs 促进了 PDAC 的进展和免疫细胞功能障碍。
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引用次数: 0
Expression of Concern: Durable Suppression of Acquired MEK Inhibitor Resistance in Cancer by Sequestering MEK from ERK and Promoting Antitumor T-cell Immunity. 表达关切:通过将 MEK 与 ERK 封闭并促进抗肿瘤 T 细胞免疫,持久抑制癌症中获得性 MEK 抑制剂抗药性。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1158/2159-8290.CD-24-0613
Aayoung Hong, Marco Piva, Sixue Liu, Willy Hugo, Shirley H Lomeli, Vincent Zoete, Christopher E Randolph, Zhentao Yang, Yan Wang, Jordan J Lee, Skylar J Lo, Lu Sun, Agustin Vega-Crespo, Alejandro J Garcia, David B Shackelford, Steven M Dubinett, Philip O Scumpia, Stephanie D Byrum, Alan J Tackett, Timothy R Donahue, Olivier Michielin, Sheri L Holmen, Antoni Ribas, Gatien Moriceau, Roger S Lo
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引用次数: 0
IL2 Targeted to CD8+ T Cells Promotes Robust Effector T-cell Responses and Potent Antitumor Immunity. 针对 CD8+ T 细胞的 IL-2 可促进强大的效应 T 细胞反应和强效抗肿瘤免疫。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-07-01 DOI: 10.1158/2159-8290.CD-23-1266
Kelly D Moynihan, Manu P Kumar, Hussein Sultan, Danielle C Pappas, Terrence Park, S Michael Chin, Paul Bessette, Ruth Y Lan, Henry C Nguyen, Nathan D Mathewson, Irene Ni, Wei Chen, Yonghee Lee, Sindy Liao-Chan, Jessie Chen, Ton N M Schumacher, Robert D Schreiber, Yik A Yeung, Ivana M Djuretic

IL2 signals pleiotropically on diverse cell types, some of which contribute to therapeutic activity against tumors, whereas others drive undesired activity, such as immunosuppression or toxicity. We explored the theory that targeting of IL2 to CD8+ T cells, which are key antitumor effectors, could enhance its therapeutic index. To this aim, we developed AB248, a CD8 cis-targeted IL2 that demonstrates over 500-fold preference for CD8+ T cells over natural killer and regulatory T cells (Tregs), which may contribute to toxicity and immunosuppression, respectively. AB248 recapitulated IL2's effects on CD8+ T cells in vitro and induced selective expansion of CD8+T cells in primates. In mice, an AB248 surrogate demonstrated superior antitumor activity and enhanced tolerability as compared with an untargeted IL2Rβγ agonist. Efficacy was associated with the expansion and phenotypic enhancement of tumor-infiltrating CD8+ T cells, including the emergence of a "better effector" population. These data support the potential utility of AB248 in clinical settings. Significance: The full potential of IL2 therapy remains to be unlocked. We demonstrate that toxicity can be decoupled from antitumor activity in preclinical models by limiting IL2 signaling to CD8+ T cells, supporting the development of CD8+ T cell-selective IL2 for the treatment of cancer. See related article by Kaptein et al. p. 1226.

IL-2对不同类型的细胞产生多重信号,其中一些有助于提高抗肿瘤治疗活性,而另一些则会产生不良活性,如免疫抑制或毒性。我们探索的理论是,将 IL-2 靶向作为关键抗肿瘤效应因子的 CD8+ T 细胞,可以提高 IL-2 的治疗指数。为此,我们开发了CD8顺式靶向IL-2 AB248,它对CD8+ T细胞的偏好超过NK和Treg细胞500倍,而NK和Treg细胞可能分别导致毒性和免疫抑制。AB248 在体外再现了 IL-2 对 CD8+ T 细胞的作用,并在灵长类动物中诱导 CD8+ T 细胞的选择性扩增。在小鼠体内,AB248替代物与非靶向IL-2RBy激动剂相比,表现出更强的抗肿瘤活性和耐受性。疗效与肿瘤浸润性 CD8+ T 细胞的扩增和表型增强有关,包括 "更好效应 "群体的出现。这些数据支持AB248在临床中的潜在用途。
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引用次数: 0
The history of chromosomal instability in genome doubled tumors 基因组加倍肿瘤中染色体不稳定性的历史
IF 28.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-06-29 DOI: 10.1158/2159-8290.cd-23-1249
Toby M. Baker, Siqi Lai, Andrew R. Lynch, Tom Lesluyes, Haixi Yan, Huw A. Ogilvie, Annelien Verfaillie, Stefan Dentro, Amy L. Bowes, Nischalan Pillay, Adrienne M. Flanagan, Charles Swanton, Paul T. Spellman, Maxime Tarabichi, Peter Van Loo
Tumors frequently display high chromosomal instability and contain multiple copies of genomic regions. Here, we describe GRITIC, a generic method for timing genomic gains leading to complex copy number states, using single-sample bulk whole-genome sequencing data. By applying GRITIC to 6,091 tumors, we found that non-parsimonious evolution is frequent in the formation of complex copy number states in genome-doubled tumors. We measured chromosomal instability before and after genome duplication in human tumors and found that late genome doubling was followed by an increase in the rate of copy number gain. Copy number gains often accumulate as punctuated bursts, commonly after genome doubling. We infer that genome duplications typically affect the landscape of copy number losses, while only minimally impacting copy number gains. In summary, GRITIC is a novel copy number gain timing framework that permits the analysis of copy number evolution in chromosomally unstable tumors.
肿瘤经常表现出高度的染色体不稳定性,并包含多个基因组区域拷贝。在这里,我们介绍了 GRITIC,这是一种利用单样本批量全基因组测序数据对导致复杂拷贝数状态的基因组增益进行计时的通用方法。通过对 6091 例肿瘤应用 GRITIC,我们发现在基因组双倍的肿瘤中,非拟合进化在复杂拷贝数状态的形成过程中非常频繁。我们测量了人类肿瘤基因组复制前后的染色体不稳定性,发现晚期基因组倍增后,拷贝数增殖率增加。拷贝数增殖通常在基因组倍增后以点状爆发的形式累积。我们推断,基因组复制通常会影响拷贝数丢失的情况,而对拷贝数增加的影响很小。总之,GRITIC 是一个新颖的拷贝数增益时间框架,可以分析染色体不稳定肿瘤的拷贝数演变。
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引用次数: 0
Deep-Learning Model for Tumor-Type Prediction Using Targeted Clinical Genomic Sequencing Data. 利用靶向临床基因组测序数据进行肿瘤类型预测的深度学习模型。
IF 29.7 1区 医学 Q1 Medicine Pub Date : 2024-06-03 DOI: 10.1158/2159-8290.CD-23-0996
Madison Darmofal, Shalabh Suman, Gurnit Atwal, Michael Toomey, Jie-Fu Chen, Jason C Chang, Efsevia Vakiani, Anna M Varghese, Anoop Balakrishnan Rema, Aijazuddin Syed, Nikolaus Schultz, Michael F Berger, Quaid Morris

Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor-type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole-genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a data set of 39,787 solid tumors sequenced using a clinically targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivaling the performance of WGS-based methods. GDD-ENS can also guide diagnoses of rare type and cancers of unknown primary and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows could provide clinically relevant tumor-type predictions to guide treatment decisions in real time.

Significance: We describe a highly accurate tumor-type prediction model, designed specifically for clinical implementation. Our model relies only on widely used cancer gene panel sequencing data, predicts across 38 distinct cancer types, and supports integration of patient-specific nongenomic information for enhanced decision support in challenging diagnostic situations. See related commentary by Garg, p. 906. This article is featured in Selected Articles from This Issue, p. 897.

肿瘤类型可指导癌症的临床治疗决策,但基于组织学的诊断仍具有挑战性。基因组改变对肿瘤类型有很高的诊断价值,根据基因组特征训练的肿瘤类型分类器已经得到了探索,但最准确的方法在临床上并不可行,因为这些方法依赖于从全基因组测序(WGS)中获得的特征,或在有限的癌症类型中进行预测。我们利用来自39,787个实体瘤数据集的基因组特征,使用临床靶向癌症基因面板进行测序,开发出基因组衍生诊断组合(GDD-ES):一种使用深度神经网络进行肿瘤类型分类的超参数组合。GDD-ENS 对 38 种癌症类型的高置信度预测准确率达到 93%,可与基于 WGS 的方法相媲美。GDD-ENS 还能指导罕见类型和原发灶不明癌症的诊断,并结合患者特定的临床信息改进预测。总之,将 GDD-ENS 整合到前瞻性临床测序工作流程中,可以提供与临床相关的肿瘤类型预测,实时指导治疗决策。
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引用次数: 0
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Cancer discovery
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