The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis. Identifying circadian therapeutic targets could facilitate the development of new treatments that leverage circadian modulation to ablate tumor-resident CSCs, inhibit tumor metastasis and enhance response to current therapies. Barker and colleagues discuss the interplay between circadian rhythm, the tumor microenvironment and stem cells and how these are linked to metastasis as well as how these interactions could be clinically relevant.
{"title":"Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis","authors":"Yu Wang, Rajesh Narasimamurthy, Meng Qu, Nuolin Shi, Haidong Guo, Yuezhen Xue, Nick Barker","doi":"10.1038/s43018-024-00759-4","DOIUrl":"10.1038/s43018-024-00759-4","url":null,"abstract":"The circadian clock regulates daily rhythms of numerous physiological activities through tightly coordinated modulation of gene expression and biochemical functions. Circadian disruption is associated with enhanced tumor formation and metastasis via dysregulation of key biological processes and modulation of cancer stem cells (CSCs) and their specialized microenvironment. Here, we review how the circadian clock influences CSCs and their local tumor niches in the context of different stages of tumor metastasis. Identifying circadian therapeutic targets could facilitate the development of new treatments that leverage circadian modulation to ablate tumor-resident CSCs, inhibit tumor metastasis and enhance response to current therapies. Barker and colleagues discuss the interplay between circadian rhythm, the tumor microenvironment and stem cells and how these are linked to metastasis as well as how these interactions could be clinically relevant.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":22.7,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140669887","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-19DOI: 10.1038/s43018-024-00763-8
Michael Rade, Nora Grieb, Ronald Weiss, Jaren Sia, Luise Fischer, Patrick Born, Andreas Boldt, Stephan Fricke, Paul Franz, Jonathan Scolnick, Lakshmi Venkatraman, Stacy Xu, Christina Kloetzer, Simone Heyn, Anne Sophie Kubasch, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Birthe Schetschorke, Saskia Hell, Sebastian Schwind, Klaus H. Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Ulrike Köhl, Uwe Platzbecker, Kristin Reiche, Vladan Vucinic, Maximilian Merz
Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8+ T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma. Merz and colleagues perform single-cell multiomic analysis of mononuclear cells isolated from individuals receiving BCMA-directed CAR T cell therapy for myeloma and show that nonresponders are characterized by an immune-suppressive microenvironment.
目前还缺少能预测复发/难治性多发性骨髓瘤患者对嵌合抗原受体（CAR）T细胞的反应和耐药性的标志物。我们在应用经批准的 B 细胞成熟抗原导向 CAR T 细胞前后，对从外周血和骨髓中分离的单核细胞进行了单细胞多组学分析，以确定与耐药性和早期复发相关的标记物。在进行白细胞清除时发现了应答者和非应答者之间的差异。无应答者的免疫抑制微环境表现为表达免疫检查点分子 CD39 的单核细胞数量增加，CD8+ T 细胞和自然杀伤细胞功能受到抑制。与低/中度扩增克隆相比，CAR T 细胞的分析表明，高扩增克隆具有细胞毒性和衰竭表型。我们确定了 CAR T 细胞的潜在免疫疗法靶点，如 PD1，以改善其功能和持久性。我们的工作提供了证据，证明免疫抑制微环境会导致多发性骨髓瘤患者对CAR T细胞疗法产生耐药性。
{"title":"Single-cell multiomic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma","authors":"Michael Rade, Nora Grieb, Ronald Weiss, Jaren Sia, Luise Fischer, Patrick Born, Andreas Boldt, Stephan Fricke, Paul Franz, Jonathan Scolnick, Lakshmi Venkatraman, Stacy Xu, Christina Kloetzer, Simone Heyn, Anne Sophie Kubasch, Ronny Baber, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Jule Ussmann, Birthe Schetschorke, Saskia Hell, Sebastian Schwind, Klaus H. Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrich Sack, Ulrike Köhl, Uwe Platzbecker, Kristin Reiche, Vladan Vucinic, Maximilian Merz","doi":"10.1038/s43018-024-00763-8","DOIUrl":"10.1038/s43018-024-00763-8","url":null,"abstract":"Markers that predict response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected mononuclear cells isolated from peripheral blood and bone marrow before and after the application of approved B cell maturation antigen-directed CAR T cells to single-cell multiomic analyses to identify markers associated with resistance and early relapse. Differences between responders and nonresponders were identified at the time of leukapheresis. Nonresponders showed an immunosuppressive microenvironment characterized by increased numbers of monocytes expressing the immune checkpoint molecule CD39 and suppressed CD8+ T cell and natural killer cell function. Analysis of CAR T cells showed cytotoxic and exhausted phenotypes in hyperexpanded clones compared to low/intermediate expanded clones. We identified potential immunotherapy targets on CAR T cells, like PD1, to improve their functionality and durability. Our work provides evidence that an immunosuppressive microenvironment causes resistance to CAR T cell therapies in multiple myeloma. Merz and colleagues perform single-cell multiomic analysis of mononuclear cells isolated from individuals receiving BCMA-directed CAR T cell therapy for myeloma and show that nonresponders are characterized by an immune-suppressive microenvironment.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140624035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-18DOI: 10.1038/s43018-024-00761-w
Hannah Lawson, James P. Holt-Martyn, Vilma Dembitz, Yuka Kabayama, Lydia M. Wang, Aarushi Bellani, Samanpreet Atwal, Nadia Saffoon, Jozef Durko, Louie N. van de Lagemaat, Azzura L. De Pace, Anthony Tumber, Thomas Corner, Eidarus Salah, Christine Arndt, Lennart Brewitz, Matthew Bowen, Louis Dubusse, Derek George, Lewis Allen, Amelie V. Guitart, Tsz Kan Fung, Chi Wai Eric So, Juerg Schwaller, Paolo Gallipoli, Donal O’Carroll, Christopher J. Schofield, Kamil R. Kranc
Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax. Lawson et al. show that genetic inactivation of Phd1 or Phd2 hinders progression of AML and compromises leukemic stem cells. They develop a selective PHD inhibitor IOX5 and show therapeutic efficacy in AML, which can be potentiated with venetoclax.
{"title":"The selective prolyl hydroxylase inhibitor IOX5 stabilizes HIF-1α and compromises development and progression of acute myeloid leukemia","authors":"Hannah Lawson, James P. Holt-Martyn, Vilma Dembitz, Yuka Kabayama, Lydia M. Wang, Aarushi Bellani, Samanpreet Atwal, Nadia Saffoon, Jozef Durko, Louie N. van de Lagemaat, Azzura L. De Pace, Anthony Tumber, Thomas Corner, Eidarus Salah, Christine Arndt, Lennart Brewitz, Matthew Bowen, Louis Dubusse, Derek George, Lewis Allen, Amelie V. Guitart, Tsz Kan Fung, Chi Wai Eric So, Juerg Schwaller, Paolo Gallipoli, Donal O’Carroll, Christopher J. Schofield, Kamil R. Kranc","doi":"10.1038/s43018-024-00761-w","DOIUrl":"10.1038/s43018-024-00761-w","url":null,"abstract":"Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, the therapeutic tractability of the hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation of HIF-1α/HIF-2α promotes AML, a possible clinical strategy is to target the HIF-prolyl hydroxylases (PHDs), which promote HIF-1α/HIF-2α degradation. Here, we reveal that genetic inactivation of Phd1/Phd2 hinders AML initiation and progression, without impacting normal hematopoiesis. We investigated clinically used PHD inhibitors and a new selective PHD inhibitor (IOX5), to stabilize HIF-α in AML cells. PHD inhibition compromises AML in a HIF-1α-dependent manner to disable pro-leukemogenic pathways, re-program metabolism and induce apoptosis, in part via upregulation of BNIP3. Notably, concurrent inhibition of BCL-2 by venetoclax potentiates the anti-leukemic effect of PHD inhibition. Thus, PHD inhibition, with consequent HIF-1α stabilization, is a promising nontoxic strategy for AML, including in combination with venetoclax. Lawson et al. show that genetic inactivation of Phd1 or Phd2 hinders progression of AML and compromises leukemic stem cells. They develop a selective PHD inhibitor IOX5 and show therapeutic efficacy in AML, which can be potentiated with venetoclax.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00761-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140608842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-18DOI: 10.1038/s43018-024-00756-7
Sanju Sinha, Rahulsimham Vegesna, Sumit Mukherjee, Ashwin V. Kammula, Saugato Rahman Dhruba, Wei Wu, D. Lucas Kerr, Nishanth Ulhas Nair, Matthew G. Jones, Nir Yosef, Oleg V. Stroganov, Ivan Grishagin, Kenneth D. Aldape, Collin M. Blakely, Peng Jiang, Craig J. Thomas, Cyril H. Benes, Trever G. Bivona, Alejandro A. Schäffer, Eytan Ruppin
Tailoring optimal treatment for individual cancer patients remains a significant challenge. To address this issue, we developed PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology), a precision oncology computational pipeline. Our approach uses publicly available matched bulk and single-cell (sc) expression profiles from large-scale cell-line drug screens. These profiles help build treatment response models based on patients’ sc-tumor transcriptomics. PERCEPTION demonstrates success in predicting responses to targeted therapies in cultured and patient-tumor-derived primary cells, as well as in two clinical trials for multiple myeloma and breast cancer. It also captures the resistance development in patients with lung cancer treated with tyrosine kinase inhibitors. PERCEPTION outperforms published state-of-the-art sc-based and bulk-based predictors in all clinical cohorts. PERCEPTION is accessible at https://github.com/ruppinlab/PERCEPTION . Our work, showcasing patient stratification using sc-expression profiles of their tumors, will encourage the adoption of sc-omics profiling in clinical settings, enhancing precision oncology tools based on sc-omics. Sinha and colleagues present PERCEPTION, a precision oncology computational pipeline that can predict the response and resistance of patients by analyzing single-cell transcriptomic data from their tumor samples.
为癌症患者量身定制最佳治疗方案仍是一项重大挑战。为了解决这个问题，我们开发了 PERCEPTION（PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology，基于单细胞表达的肿瘤精准治疗规划）--一个肿瘤精准治疗计算管道。我们的方法使用从大规模细胞系药物筛选中公开获得的匹配批量和单细胞（sc）表达谱。这些图谱有助于根据患者的肿瘤转录组学建立治疗反应模型。PERCEPTION 成功预测了培养细胞和患者肿瘤原代细胞对靶向疗法的反应，并在多发性骨髓瘤和乳腺癌的两项临床试验中得到了验证。它还捕捉到了接受酪氨酸激酶抑制剂治疗的肺癌患者的耐药性发展情况。在所有临床队列中，PERCEPTION 都优于已发表的最先进的基于 sc 和基于 bulk 的预测指标。PERCEPTION可在https://github.com/ruppinlab/PERCEPTION。我们的工作展示了利用肿瘤的sc表达谱对患者进行分层，这将鼓励在临床环境中采用sc组学分析，增强基于sc组学的精准肿瘤学工具。
{"title":"PERCEPTION predicts patient response and resistance to treatment using single-cell transcriptomics of their tumors","authors":"Sanju Sinha, Rahulsimham Vegesna, Sumit Mukherjee, Ashwin V. Kammula, Saugato Rahman Dhruba, Wei Wu, D. Lucas Kerr, Nishanth Ulhas Nair, Matthew G. Jones, Nir Yosef, Oleg V. Stroganov, Ivan Grishagin, Kenneth D. Aldape, Collin M. Blakely, Peng Jiang, Craig J. Thomas, Cyril H. Benes, Trever G. Bivona, Alejandro A. Schäffer, Eytan Ruppin","doi":"10.1038/s43018-024-00756-7","DOIUrl":"10.1038/s43018-024-00756-7","url":null,"abstract":"Tailoring optimal treatment for individual cancer patients remains a significant challenge. To address this issue, we developed PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology), a precision oncology computational pipeline. Our approach uses publicly available matched bulk and single-cell (sc) expression profiles from large-scale cell-line drug screens. These profiles help build treatment response models based on patients’ sc-tumor transcriptomics. PERCEPTION demonstrates success in predicting responses to targeted therapies in cultured and patient-tumor-derived primary cells, as well as in two clinical trials for multiple myeloma and breast cancer. It also captures the resistance development in patients with lung cancer treated with tyrosine kinase inhibitors. PERCEPTION outperforms published state-of-the-art sc-based and bulk-based predictors in all clinical cohorts. PERCEPTION is accessible at https://github.com/ruppinlab/PERCEPTION . Our work, showcasing patient stratification using sc-expression profiles of their tumors, will encourage the adoption of sc-omics profiling in clinical settings, enhancing precision oncology tools based on sc-omics. Sinha and colleagues present PERCEPTION, a precision oncology computational pipeline that can predict the response and resistance of patients by analyzing single-cell transcriptomic data from their tumor samples.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140608977","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-15DOI: 10.1038/s43018-024-00767-4
Hugh O’Brien, Max Salm, Laura T. Morton, Maciej Szukszto, Felix O’Farrell, Charlotte Boulton, Pablo D. Becker, Yardena Samuels, Charles Swanton, Marc R. Mansour, Sine Reker Hadrup, Sergio A. Quezada
{"title":"Author Correction: Breaking the performance ceiling for neoantigen immunogenicity prediction","authors":"Hugh O’Brien, Max Salm, Laura T. Morton, Maciej Szukszto, Felix O’Farrell, Charlotte Boulton, Pablo D. Becker, Yardena Samuels, Charles Swanton, Marc R. Mansour, Sine Reker Hadrup, Sergio A. Quezada","doi":"10.1038/s43018-024-00767-4","DOIUrl":"10.1038/s43018-024-00767-4","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":22.7,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00767-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140700169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-12DOI: 10.1038/s43018-024-00760-x
Xiangyu Chen, Jing Zhao, Shuai Yue, Ziyu Li, Xiang Duan, Yao Lin, Yang Yang, Junjian He, Leiqiong Gao, Zhiwei Pan, Xiaofan Yang, Xingxing Su, Min Huang, Xiao Li, Ye Zhao, Xuehui Zhang, Zhirong Li, Li Hu, Jianfang Tang, Yaxing Hao, Qin Tian, Yifei Wang, Lifan Xu, Qizhao Huang, Yingjiao Cao, Yaokai Chen, Bo Zhu, Yan Li, Fan Bai, Guozhong Zhang, Lilin Ye
Tumor-specific T cells are crucial in anti-tumor immunity and act as targets for cancer immunotherapies. However, these cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME), leading to inefficacious immunotherapies in most patients with cancer. By contrast, emerging evidence suggested that tumor-irrelevant bystander T (TBYS) cells are abundant and preserve functional memory properties in the TME. To leverage TBYS cells in the TME to eliminate tumor cells, we engineered oncolytic virus (OV) encoding TBYS epitopes (OV-BYTE) to redirect the antigen specificity of tumor cells to pre-existing TBYS cells, leading to effective tumor inhibition in multiple preclinical models. Mechanistically, OV-BYTE induced epitope spreading of tumor antigens to elicit more diverse tumor-specific T cell responses. Remarkably, the OV-BYTE strategy targeting human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory efficiently inhibited tumor progression in a human tumor cell-derived xenograft model, providing important insights into the improvement of cancer immunotherapies in a large population with a history of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination. Ye and colleagues show that an oncolytic virus that delivers tumor-irrelevant bystander T cell epitopes to tumor cells can exploit the abundant population of bystander T cells in the tumor for anti-tumor immunity and potentiate cancer immunotherapy.
肿瘤特异性 T 细胞是抗肿瘤免疫的关键，也是癌症免疫疗法的靶点。然而，这些细胞在肿瘤微环境（TME）中数量稀少、功能衰竭，导致大多数癌症患者的免疫疗法效果不佳。相比之下，新出现的证据表明，与肿瘤无关的旁观者 T 细胞（TBYS）数量丰富，并在肿瘤微环境中保留了功能记忆特性。为了利用TME中的TBYS细胞消灭肿瘤细胞，我们设计了编码TBYS表位的溶瘤病毒（OV）（OV-BYTE），将肿瘤细胞的抗原特异性重定向到预先存在的TBYS细胞，从而在多个临床前模型中有效抑制肿瘤。从机理上讲，OV-BYTE 可诱导肿瘤抗原表位扩散，从而激发更多样化的肿瘤特异性 T 细胞反应。值得注意的是，以人类严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）特异性T细胞记忆为靶点的OV-BYTE策略有效抑制了人类肿瘤细胞衍生异种移植模型中的肿瘤进展，为改善大量有SARS-CoV-2感染史或冠状病毒病2019（COVID-19）疫苗接种史的人群的癌症免疫疗法提供了重要启示。
{"title":"An oncolytic virus delivering tumor-irrelevant bystander T cell epitopes induces anti-tumor immunity and potentiates cancer immunotherapy","authors":"Xiangyu Chen, Jing Zhao, Shuai Yue, Ziyu Li, Xiang Duan, Yao Lin, Yang Yang, Junjian He, Leiqiong Gao, Zhiwei Pan, Xiaofan Yang, Xingxing Su, Min Huang, Xiao Li, Ye Zhao, Xuehui Zhang, Zhirong Li, Li Hu, Jianfang Tang, Yaxing Hao, Qin Tian, Yifei Wang, Lifan Xu, Qizhao Huang, Yingjiao Cao, Yaokai Chen, Bo Zhu, Yan Li, Fan Bai, Guozhong Zhang, Lilin Ye","doi":"10.1038/s43018-024-00760-x","DOIUrl":"10.1038/s43018-024-00760-x","url":null,"abstract":"Tumor-specific T cells are crucial in anti-tumor immunity and act as targets for cancer immunotherapies. However, these cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME), leading to inefficacious immunotherapies in most patients with cancer. By contrast, emerging evidence suggested that tumor-irrelevant bystander T (TBYS) cells are abundant and preserve functional memory properties in the TME. To leverage TBYS cells in the TME to eliminate tumor cells, we engineered oncolytic virus (OV) encoding TBYS epitopes (OV-BYTE) to redirect the antigen specificity of tumor cells to pre-existing TBYS cells, leading to effective tumor inhibition in multiple preclinical models. Mechanistically, OV-BYTE induced epitope spreading of tumor antigens to elicit more diverse tumor-specific T cell responses. Remarkably, the OV-BYTE strategy targeting human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory efficiently inhibited tumor progression in a human tumor cell-derived xenograft model, providing important insights into the improvement of cancer immunotherapies in a large population with a history of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination. Ye and colleagues show that an oncolytic virus that delivers tumor-irrelevant bystander T cell epitopes to tumor cells can exploit the abundant population of bystander T cells in the tumor for anti-tumor immunity and potentiate cancer immunotherapy.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00760-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140595291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-11DOI: 10.1038/s43018-024-00766-5
Zijie Feng, Xin He, Xuyao Zhang, Yuan Wu, Bowen Xing, Alison Knowles, Qiaonan Shan, Samuel Miller, Taylor Hojnacki, Jian Ma, Bryson W. Katona, Terence P. F. Gade, Don L. Siegel, Jörg Schrader, David C. Metz, Carl H. June, Xianxin Hua
{"title":"Author Correction: Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues","authors":"Zijie Feng, Xin He, Xuyao Zhang, Yuan Wu, Bowen Xing, Alison Knowles, Qiaonan Shan, Samuel Miller, Taylor Hojnacki, Jian Ma, Bryson W. Katona, Terence P. F. Gade, Don L. Siegel, Jörg Schrader, David C. Metz, Carl H. June, Xianxin Hua","doi":"10.1038/s43018-024-00766-5","DOIUrl":"10.1038/s43018-024-00766-5","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":22.7,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00766-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140714522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-02DOI: 10.1038/s43018-024-00754-9
Emilie A. Chapeau, Laurent Sansregret, Giorgio G. Galli, Patrick Chène, Markus Wartmann, Thanos P. Mourikis, Patricia Jaaks, Sabrina Baltschukat, Ines A. M. Barbosa, Daniel Bauer, Saskia M. Brachmann, Clara Delaunay, Claire Estadieu, Jason E. Faris, Pascal Furet, Stefanie Harlfinger, Andreas Hueber, Eloísa Jiménez Núñez, David P. Kodack, Emeline Mandon, Typhaine Martin, Yannick Mesrouze, Vincent Romanet, Clemens Scheufler, Holger Sellner, Christelle Stamm, Dario Sterker, Luca Tordella, Francesco Hofmann, Nicolas Soldermann, Tobias Schmelzle
The YAP–TEAD protein–protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP–TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP–TEAD protein–protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway. Chapeau et al. develop a nonallosteric inhibitor of the interaction between YAP and all four TEAD proteins. Treatment with the inhibitor, either as monotherapy or in combination with other treatment modalities, leads to induction of cell death in several in vivo cancer models.
{"title":"Direct and selective pharmacological disruption of the YAP–TEAD interface by IAG933 inhibits Hippo-dependent and RAS–MAPK-altered cancers","authors":"Emilie A. Chapeau, Laurent Sansregret, Giorgio G. Galli, Patrick Chène, Markus Wartmann, Thanos P. Mourikis, Patricia Jaaks, Sabrina Baltschukat, Ines A. M. Barbosa, Daniel Bauer, Saskia M. Brachmann, Clara Delaunay, Claire Estadieu, Jason E. Faris, Pascal Furet, Stefanie Harlfinger, Andreas Hueber, Eloísa Jiménez Núñez, David P. Kodack, Emeline Mandon, Typhaine Martin, Yannick Mesrouze, Vincent Romanet, Clemens Scheufler, Holger Sellner, Christelle Stamm, Dario Sterker, Luca Tordella, Francesco Hofmann, Nicolas Soldermann, Tobias Schmelzle","doi":"10.1038/s43018-024-00754-9","DOIUrl":"10.1038/s43018-024-00754-9","url":null,"abstract":"The YAP–TEAD protein–protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP–TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP–TEAD protein–protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway. Chapeau et al. develop a nonallosteric inhibitor of the interaction between YAP and all four TEAD proteins. Treatment with the inhibitor, either as monotherapy or in combination with other treatment modalities, leads to induction of cell death in several in vivo cancer models.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00754-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140595574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-02DOI: 10.1038/s43018-024-00750-z
A CRISPR dropout screen for tRNA regulators identified YRDC as the top essential gene in glioblastoma stem cells. Threonine acts as a substrate of YRDC to facilitate the N6-threonylcarbamoyladenosine (t6A) tRNA modification and shift translation toward mitosis-related genes with a codon bias. Our findings support targeting glioblastoma growth by a well-tolerated dietary therapy.
{"title":"Threonine fuels brain tumor growth through a conserved tRNA modification","authors":"","doi":"10.1038/s43018-024-00750-z","DOIUrl":"10.1038/s43018-024-00750-z","url":null,"abstract":"A CRISPR dropout screen for tRNA regulators identified YRDC as the top essential gene in glioblastoma stem cells. Threonine acts as a substrate of YRDC to facilitate the N6-threonylcarbamoyladenosine (t6A) tRNA modification and shift translation toward mitosis-related genes with a codon bias. Our findings support targeting glioblastoma growth by a well-tolerated dietary therapy.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":23.5,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140595275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-03-29DOI: 10.1038/s43018-024-00745-w
Jennifer L. Guida, Geehong Hyun, Daniel W. Belsky, Gregory T. Armstrong, Matthew J. Ehrhardt, Melissa M. Hudson, Paige A. Green, Leslie L. Robison, Brennan P. Streck, Emily S. Tonorezos, Yutaka Yasui, Carmen L. Wilson, Zhaoming Wang, Kirsten K. Ness
Survivors of childhood cancer may experience accelerated biological aging, resulting in premature frailty and death. We used seven measures of biological age in the St. Jude Lifetime (SJLIFE) Cohort to compare biological age acceleration between the SJLIFE Cohort and the third United States National Health and Nutrition Examination Survey controls, explore trajectories of biological age according to cancer treatment and type, and test associations of biological age acceleration with frailty and death (mean follow-up of 26.5 years) among survivors. Survivors of cancer aged 5% faster per year and measured, on average, 0.6–6.44 years biologically older compared to controls and 5–16 years biologically older compared to age-matched individuals at the population level. Survivors treated with hematopoietic cell transplant and vinca alkaloid chemotherapy evidenced the fastest trajectories of biological aging. Biologically, older and faster-aging survivors consistently and robustly had a higher risk of frailty and died earlier than those with slower biological aging, suggesting a potential opportunity to intervene on excess aging. Guida et al. assess seven measures of biological age in SJLIFE Cohort and reveal that survivors of cancer age faster than healthy controls and have increased risk of frailty and death. The aging trajectory is further affected by cancer type and therapy.
{"title":"Associations of seven measures of biological age acceleration with frailty and all-cause mortality among adult survivors of childhood cancer in the St. Jude Lifetime Cohort","authors":"Jennifer L. Guida, Geehong Hyun, Daniel W. Belsky, Gregory T. Armstrong, Matthew J. Ehrhardt, Melissa M. Hudson, Paige A. Green, Leslie L. Robison, Brennan P. Streck, Emily S. Tonorezos, Yutaka Yasui, Carmen L. Wilson, Zhaoming Wang, Kirsten K. Ness","doi":"10.1038/s43018-024-00745-w","DOIUrl":"10.1038/s43018-024-00745-w","url":null,"abstract":"Survivors of childhood cancer may experience accelerated biological aging, resulting in premature frailty and death. We used seven measures of biological age in the St. Jude Lifetime (SJLIFE) Cohort to compare biological age acceleration between the SJLIFE Cohort and the third United States National Health and Nutrition Examination Survey controls, explore trajectories of biological age according to cancer treatment and type, and test associations of biological age acceleration with frailty and death (mean follow-up of 26.5 years) among survivors. Survivors of cancer aged 5% faster per year and measured, on average, 0.6–6.44 years biologically older compared to controls and 5–16 years biologically older compared to age-matched individuals at the population level. Survivors treated with hematopoietic cell transplant and vinca alkaloid chemotherapy evidenced the fastest trajectories of biological aging. Biologically, older and faster-aging survivors consistently and robustly had a higher risk of frailty and died earlier than those with slower biological aging, suggesting a potential opportunity to intervene on excess aging. Guida et al. assess seven measures of biological age in SJLIFE Cohort and reveal that survivors of cancer age faster than healthy controls and have increased risk of frailty and death. The aging trajectory is further affected by cancer type and therapy.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":null,"pages":null},"PeriodicalIF":22.7,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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