Nature cancer最新文献

{"title":"Selective targeting of malignant T cells","authors":"Charles E. de Bock, Jan Cools","doi":"10.1038/s43018-024-00778-1","DOIUrl":"10.1038/s43018-024-00778-1","url":null,"abstract":"Targeted therapies that use small-molecule inhibitors for the treatment of T cell blood cancer exist only for certain subtypes, and the development of immunologically based CAR T cell therapies has been challenging. A study now exploits the fact that malignant T cells express one of two T cell receptor-β variants and investigates strategies for targeting these malignant cells while sparing half of the non-malignant T cells.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 6","pages":"823-824"},"PeriodicalIF":23.5,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180389","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}

{"title":"Constructing co-stimulation to boost TCR therapy","authors":"Julia Höbart, Jürgen Ruland","doi":"10.1038/s43018-024-00746-9","DOIUrl":"10.1038/s43018-024-00746-9","url":null,"abstract":"T cell receptor (TCR)-engineered T cells offer great promise for targeting tumor antigens in cancer therapy. A synthetic fusion protein termed 80BB, which can simultaneously activate the CD28 and 4-1BB co-stimulatory pathways, is now shown to enhance overall functionality of therapeutic TCR/CD3-dependent T cells in an antigen-agnostic manner.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 5","pages":"697-698"},"PeriodicalIF":22.7,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178546","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}

{"title":"Targeting a lineage-specific PI3Kɣ–Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule","authors":"Lois M. Kelly, Justine C. Rutter, Kevin H. Lin, Frank Ling, Matthieu Duchmann, Emmanuelle Latour, Nadia Arang, Hélène Pasquer, Duong Ho Nhat, Juliette Charles, Shane T. Killarney, Hazel X. Ang, Federica Namor, Cécile Culeux, Bérangère Lombard, Damarys Loew, Danielle L. Swaney, Nevan J. Krogan, Luc Brunel, Élodie Carretero, Pascal Verdié, Muriel Amblard, Sofiane Fodil, Tony Huynh, Marie Sebert, Lionel Adès, Emmanuel Raffoux, Nina Fenouille, Raphaël Itzykson, Camille Lobry, Lina Benajiba, Antoine Forget, Anthony R. Martin, Kris C. Wood, Alexandre Puissant","doi":"10.1038/s43018-024-00782-5","DOIUrl":"10.1038/s43018-024-00782-5","url":null,"abstract":"Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ–PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models. Puissant and colleagues identify a myeloid-restricted PIK3CG/p110γ–PIK3R5/p101 axis as a therapeutic vulnerability in acute myeloid leukemia and develop a proteolysis-targeting chimera to potently degrade PIK3CG and suppress AML progression.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 7","pages":"1082-1101"},"PeriodicalIF":23.5,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178109","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}

{"title":"APOBEC3 upregulation drives gemcitabine resistance","authors":"John Maciejowski, Taha Mohamed","doi":"10.1038/s43018-024-00755-8","DOIUrl":"10.1038/s43018-024-00755-8","url":null,"abstract":"Gemcitabine is a widely used chemotherapy drug that acts by targeting DNA replication. Understanding why many tumors are unresponsive to gemcitabine is a clinical challenge. A new study in Nature Cancer reports that upregulation of the cytidine deaminases APOBEC3C and APOBEC3D facilitates resistance to gemcitabine by protecting cells against DNA replication stress.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 6","pages":"818-820"},"PeriodicalIF":23.5,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080754","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}

{"title":"Author Correction: Identification of a clinically efficacious CAR T cell subset in diffuse large B cell lymphoma by dynamic multidimensional single-cell profiling","authors":"Ali Rezvan, Gabrielle Romain, Mohsen Fathi, Darren Heeke, Melisa Martinez-Paniagua, Xingyue An, Irfan N. Bandey, Melisa J. Montalvo, Jay R. T. Adolacion, Arash Saeedi, Fatemeh Sadeghi, Kristen Fousek, Nahum Puebla-Osorio, Laurence J. N. Cooper, Chantale Bernatchez, Harjeet Singh, Nabil Ahmed, Mike Mattie, Adrian Bot, Sattva Neelapu, Navin Varadarajan","doi":"10.1038/s43018-024-00786-1","DOIUrl":"10.1038/s43018-024-00786-1","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 6","pages":"954-954"},"PeriodicalIF":23.5,"publicationDate":"2024-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00786-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141080834","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}

{"title":"Targeting TAK1 in microglia to treat CAR T cell neurotoxicity","authors":"","doi":"10.1038/s43018-024-00765-6","DOIUrl":"10.1038/s43018-024-00765-6","url":null,"abstract":"We profiled microglia using single-cell multi-omics techniques in lymphoma-bearing mice and patients who developed neurotoxicity after CAR19 T cell transfer. We discovered that microglial activation after CAR19 T cell infusion was mediated mainly by the kinase TAK1, which suggests that targeting TAK1 in patients receiving CAR19 T cell-based cancer immunotherapy could treat neurotoxicity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 8","pages":"1143-1144"},"PeriodicalIF":23.5,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071548","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}

{"title":"Author Correction: Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress","authors":"Xihui Liu, Suryavathi Viswanadhapalli, Shourya Kumar, Tae-Kyung Lee, Andrew Moore, Shihong Ma, Liping Chen, Michael Hsieh, Mengxing Li, Gangadhara R. Sareddy, Karla Parra, Eliot B. Blatt, Tanner C. Reese, Yuting Zhao, Annabel Chang, Hui Yan, Zhenming Xu, Uday P. Pratap, Zexuan Liu, Carlos M. Roggero, Zhenqiu Tan, Susan T. Weintraub, Yan Peng, Rajeshwar R. Tekmal, Carlos L. Arteaga, Jennifer Lippincott-Schwartz, Ratna K. Vadlamudi, Jung-Mo Ahn, Ganesh V. Raj","doi":"10.1038/s43018-024-00783-4","DOIUrl":"10.1038/s43018-024-00783-4","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 6","pages":"953-953"},"PeriodicalIF":23.5,"publicationDate":"2024-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11208131/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141071546","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}

{"title":"Quantum computing for oncology","authors":"Siddhi Ramesh, Teague Tomesh, Samantha J. Riesenfeld, Frederic T. Chong, Alexander T. Pearson","doi":"10.1038/s43018-024-00770-9","DOIUrl":"10.1038/s43018-024-00770-9","url":null,"abstract":"As quantum technology advances, it holds immense potential to accelerate oncology discovery through enhanced molecular modeling, genomic analysis, medical imaging, and quantum sensing.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 6","pages":"811-816"},"PeriodicalIF":23.5,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140958363","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}

{"title":"Identification of a clinically efficacious CAR T cell subset in diffuse large B cell lymphoma by dynamic multidimensional single-cell profiling","authors":"Ali Rezvan, Gabrielle Romain, Mohsen Fathi, Darren Heeke, Melisa Martinez-Paniagua, Xingyue An, Irfan N. Bandey, Melisa J. Montalvo, Jay R. T. Adolacion, Arash Saeedi, Fatemeh Sadeghi, Kristen Fousek, Nahum Puebla-Osorio, Laurence J. N. Cooper, Chantale Bernatchez, Harjeet Singh, Nabil Ahmed, Mike Mattie, Adrian Bot, Sattva Neelapu, Navin Varadarajan","doi":"10.1038/s43018-024-00768-3","DOIUrl":"10.1038/s43018-024-00768-3","url":null,"abstract":"Chimeric antigen receptor (CAR) T cells used for the treatment of B cell malignancies can identify T cell subsets with superior clinical activity. Here, using infusion products of individuals with large B cell lymphoma, we integrated functional profiling using timelapse imaging microscopy in nanowell grids with subcellular profiling and single-cell RNA sequencing to identify a signature of multifunctional CD8+ T cells (CD8-fit T cells). CD8-fit T cells are capable of migration and serial killing and harbor balanced mitochondrial and lysosomal volumes. Using independent datasets, we validate that CD8-fit T cells (1) are present premanufacture and are associated with clinical responses in individuals treated with axicabtagene ciloleucel, (2) longitudinally persist in individuals after treatment with CAR T cells and (3) are tumor migrating cytolytic cells capable of intratumoral expansion in solid tumors. Our results demonstrate the power of multimodal integration of single-cell functional assessments for the discovery and application of CD8-fit T cells as a T cell subset with optimal fitness in cell therapy. Rezvan and colleagues profile the infusion product from individuals with DLBCL treated with CAR T cells and integrate functional profiling by timelapse imaging microscopy and scRNA-seq to identify a signature of migratory CD8+ T cells associated with response.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 7","pages":"1010-1023"},"PeriodicalIF":23.5,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140939552","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}

{"title":"Targeting TGFβ-activated kinase-1 activation in microglia reduces CAR T immune effector cell-associated neurotoxicity syndrome","authors":"Janaki Manoja Vinnakota, Francesca Biavasco, Marius Schwabenland, Chintan Chhatbar, Rachael C. Adams, Daniel Erny, Sandra Duquesne, Nadia El Khawanky, Dominik Schmidt, Viktor Fetsch, Alexander Zähringer, Henrike Salié, Dimitrios Athanassopoulos, Lukas M. Braun, Nora R. Javorniczky, Jenny N. H. G. Ho, Katrin Kierdorf, Reinhard Marks, Ralph Wäsch, Federico Simonetta, Geoffroy Andrieux, Dietmar Pfeifer, Gianni Monaco, Christian Capitini, Terry J. Fry, Thomas Blank, Bruce R. Blazar, Eva Wagner, Matthias Theobald, Clemens Sommer, Matthias Stelljes, Christian Reicherts, Astrid Jeibmann, Jens Schittenhelm, Camelia-Maria Monoranu, Andreas Rosenwald, Martin Kortüm, Leo Rasche, Hermann Einsele, Philipp T. Meyer, Joachim Brumberg, Simon Völkl, Andreas Mackensen, Roland Coras, Michael von Bergwelt-Baildon, Nathalie L. Albert, Laura M. Bartos, Matthias Brendel, Adrien Holzgreve, Matthias Mack, Melanie Boerries, Crystal L. Mackall, Justus Duyster, Philipp Henneke, Josef Priller, Natalie Köhler, Felix Strübing, Bertram Bengsch, Marco Ruella, Marion Subklewe, Louisa von Baumgarten, Saar Gill, Marco Prinz, Robert Zeiser","doi":"10.1038/s43018-024-00764-7","DOIUrl":"10.1038/s43018-024-00764-7","url":null,"abstract":"Cancer immunotherapy with chimeric antigen receptor (CAR) T cells can cause immune effector cell-associated neurotoxicity syndrome (ICANS). However, the molecular mechanisms leading to ICANS are not well understood. Here we examined the role of microglia using mouse models and cohorts of individuals with ICANS. CD19-directed CAR (CAR19) T cell transfer in B cell lymphoma-bearing mice caused microglia activation and neurocognitive deficits. The TGFβ-activated kinase-1 (TAK1)–NF-κB–p38 MAPK pathway was activated in microglia after CAR19 T cell transfer. Pharmacological TAK1 inhibition or genetic Tak1 deletion in microglia using Cx3cr1CreER:Tak1fl/fl mice resulted in reduced microglia activation and improved neurocognitive activity. TAK1 inhibition allowed for potent CAR19-induced antilymphoma effects. Individuals with ICANS exhibited microglia activation in vivo when studied by translocator protein positron emission tomography, and imaging mass cytometry revealed a shift from resting to activated microglia. In summary, we prove a role for microglia in ICANS pathophysiology, identify the TAK1–NF-κB–p38 MAPK axis as a pathogenic signaling pathway and provide a rationale to test TAK1 inhibition in a clinical trial for ICANS prevention after CAR19 T cell-based cancer immunotherapy. Zeiser and colleagues show that CAR T cell therapy results in upregulation of the TGFβ-activated kinase-1 (TAK1)–NF-κB–p38 MAPK pathway in microglia, causing neurocognitive defects, and find that TAK1 inhibition can reduce immune effector cell-associated neurotoxicity syndrome.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 8","pages":"1227-1249"},"PeriodicalIF":23.5,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140916398","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}