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Microengineered in vitro CAR T cell screens and assays. 微工程体外CAR - T细胞筛选和分析。
Cell systems Pub Date : 2024-12-18 DOI: 10.1016/j.cels.2024.11.011
Jaehoon Kim, Susan Napier Thomas
{"title":"Microengineered in vitro CAR T cell screens and assays.","authors":"Jaehoon Kim, Susan Napier Thomas","doi":"10.1016/j.cels.2024.11.011","DOIUrl":"10.1016/j.cels.2024.11.011","url":null,"abstract":"<p><p>Established and emergent microengineered in vitro systems enable the evaluation of chimeric antigen receptor (CAR) T cell product purity, avidity, and functionality. Here, we describe such systems and how they have been used to optimize CAR T cell products by selecting highly viable cells, eliminating off-target cells, and tailoring avidity to balance efficacy and safety. The future of CAR T cell therapy development and manufacturing is expected to be anchored in a cyclical process that integrates multiple high-throughput and patient-centered techniques for identifying, enriching, and evaluating T cell subtypes. This article explores several cutting-edge platforms and methodologies relevant to these processes.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":"15 12","pages":"1209-1224"},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866650","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Emerging approaches for T cell-stimulating platform development. T细胞刺激平台开发的新方法。
Cell systems Pub Date : 2024-12-18 DOI: 10.1016/j.cels.2024.11.007
Emily Ariail, Nikol Garcia Espinoza, A Carson Stephenson, Jamie B Spangler
{"title":"Emerging approaches for T cell-stimulating platform development.","authors":"Emily Ariail, Nikol Garcia Espinoza, A Carson Stephenson, Jamie B Spangler","doi":"10.1016/j.cels.2024.11.007","DOIUrl":"10.1016/j.cels.2024.11.007","url":null,"abstract":"<p><p>T cells are key mediators of the adaptive immune response, playing both direct and supporting roles in the destruction of foreign pathogenic threats as well as pathologically transformed host cells. The natural process through which T cells are activated requires coordinated molecular interactions between antigen-presenting cells and T cells. Promising advances in biomaterial design have catalyzed the development of artificial platforms that mimic the natural process of T cell stimulation, both to bolster the performance of cell therapies by activating T cells ex vivo prior to adoptive cell transfer and to directly activate T cells in vivo as off-the-shelf treatments. This review focuses on innovative strategies in T cell-stimulating platform design for applications in cancer therapy. We specifically highlight progress in bead-based artificial antigen-presenting cell engineering, hydrogel-based scaffolds, DNA-based systems, alternative polymeric strategies, and soluble activation approaches. Collectively, these advances are expanding the repertoire of tools for targeted immune activation.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":"15 12","pages":"1198-1208"},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11665896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
What unique insights can modeling approaches capture about the immune system? 建模方法可以获得关于免疫系统的哪些独特见解?
Cell systems Pub Date : 2024-12-18 DOI: 10.1016/j.cels.2024.11.016
Hao Yuan Kueh, Andreas Handel, Alexander Hoffmann, Diego Chowell, Rachel A Gottschalk, Harinder Singh, Ronald N Germain, Martin Meier-Schellersheim, Kathryn Miller-Jensen, Grégoire Altan-Bonnet
{"title":"What unique insights can modeling approaches capture about the immune system?","authors":"Hao Yuan Kueh, Andreas Handel, Alexander Hoffmann, Diego Chowell, Rachel A Gottschalk, Harinder Singh, Ronald N Germain, Martin Meier-Schellersheim, Kathryn Miller-Jensen, Grégoire Altan-Bonnet","doi":"10.1016/j.cels.2024.11.016","DOIUrl":"https://doi.org/10.1016/j.cels.2024.11.016","url":null,"abstract":"","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":"15 12","pages":"1148-1152"},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening. 全基因组光池筛选鉴定细胞内STING转运调节因子的分类和功能表征。
Cell systems Pub Date : 2024-12-18 Epub Date: 2024-12-09 DOI: 10.1016/j.cels.2024.11.004
Matteo Gentili, Rebecca J Carlson, Bingxu Liu, Quentin Hellier, Jocelyn Andrews, Yue Qin, Paul C Blainey, Nir Hacohen
{"title":"Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening.","authors":"Matteo Gentili, Rebecca J Carlson, Bingxu Liu, Quentin Hellier, Jocelyn Andrews, Yue Qin, Paul C Blainey, Nir Hacohen","doi":"10.1016/j.cels.2024.11.004","DOIUrl":"10.1016/j.cels.2024.11.004","url":null,"abstract":"<p><p>Stimulator of interferon genes (STING) traffics across intracellular compartments to trigger innate responses. Mutations in factors regulating this process lead to inflammatory disorders. To systematically identify factors involved in STING trafficking, we performed a genome-wide optical pooled screen (OPS). Based on the subcellular localization of STING in 45 million cells, we defined 464 clusters of gene perturbations based on their cellular phenotypes. A secondary, higher-dimensional OPS identified 73 finer clusters. We show that the loss of the gene of unknown function C19orf25, which clustered with USE1, a protein involved in Golgi-to-endoplasmic reticulum (ER) transport, enhances STING signaling. Additionally, HOPS deficiency delayed STING degradation and consequently increased signaling. Similarly, GARP/RIC1-RGP1 loss increased STING signaling by delaying STING Golgi exit. Our findings demonstrate that genome-wide genotype-phenotype maps based on high-content cell imaging outperform other screening approaches and provide a community resource for mining factors that impact STING trafficking and other cellular processes.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"1264-1277.e8"},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142808784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Metabolic immunoengineering approaches to enhance CD8+ T cell-based cancer immunotherapy. 代谢免疫工程方法增强基于CD8+ T细胞的癌症免疫治疗。
Cell systems Pub Date : 2024-12-18 DOI: 10.1016/j.cels.2024.11.010
Bing Feng, Rongrong Li, Weilin Li, Li Tang
{"title":"Metabolic immunoengineering approaches to enhance CD8<sup>+</sup> T cell-based cancer immunotherapy.","authors":"Bing Feng, Rongrong Li, Weilin Li, Li Tang","doi":"10.1016/j.cels.2024.11.010","DOIUrl":"10.1016/j.cels.2024.11.010","url":null,"abstract":"<p><p>Many cancer immunotherapies rely on robust CD8<sup>+</sup> T cells capable of eliminating cancer cells and establishing long-term tumor control. Recent insights into immunometabolism highlight the importance of nutrients and metabolites in T cell activation and differentiation. Within the tumor microenvironment (TME), CD8<sup>+</sup> tumor-infiltrating lymphocytes (TILs) undergo metabolic adaptations to survive but compromise their effector function and differentiation. Targeting metabolism holds promise for enhancing CD8<sup>+</sup> T cell-mediated antitumor immunity. Here, we overview the metabolic features of CD8<sup>+</sup> TILs and their impact on T cell effector function and differentiation. We also highlight immunoengineering strategies by leveraging the Yin-Yang of metabolic modulation for improving cancer immunotherapy.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":"15 12","pages":"1225-1244"},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866648","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Predicting adaptive immune receptor specificities by machine learning is a data generation problem. 通过机器学习预测适应性免疫受体特异性是一个数据生成问题。
Cell systems Pub Date : 2024-12-18 DOI: 10.1016/j.cels.2024.11.008
Derek M Mason, Sai T Reddy
{"title":"Predicting adaptive immune receptor specificities by machine learning is a data generation problem.","authors":"Derek M Mason, Sai T Reddy","doi":"10.1016/j.cels.2024.11.008","DOIUrl":"10.1016/j.cels.2024.11.008","url":null,"abstract":"<p><p>Determining the specificity of adaptive immune receptors-B cell receptors (BCRs), their secreted form antibodies, and T cell receptors (TCRs)-is critical for understanding immune responses and advancing immunotherapy and drug discovery. Immune receptors exhibit extensive diversity in their variable domains, enabling them to interact with a plethora of antigens. Despite the significant progress made by AI tools such as AlphaFold in predicting protein structures, challenges remain in accurately modeling the structure and specificity of immune receptors, primarily due to the limited availability of high-quality crystal structures and the complexity of immune receptor-antigen interactions. In this perspective, we highlight recent advancements in sequence-based and structure-based data generation for immune receptors, which are crucial for training machine learning models that predict receptor specificity. We discuss the current bottlenecks and potential future directions in generating and utilizing high-dimensional datasets for predicting and designing the specificity of antibodies and TCRs.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":"15 12","pages":"1190-1197"},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Turing patterns with cellular computers. 图灵模式与细胞计算机。
Cell systems Pub Date : 2024-12-18 DOI: 10.1016/j.cels.2024.11.015
Lewis Grozinger, Ángel Goñi-Moreno
{"title":"Turing patterns with cellular computers.","authors":"Lewis Grozinger, Ángel Goñi-Moreno","doi":"10.1016/j.cels.2024.11.015","DOIUrl":"https://doi.org/10.1016/j.cels.2024.11.015","url":null,"abstract":"<p><p>Turing patterns are a key theoretical foundation for understanding organ development and organization. While they have been found to occur in natural systems, implementing new biological systems that form Turing patterns has remained challenging. To address this, Tica et al.<sup>1</sup> used synthetic genetic networks to engineer living cellular computers that successfully generate Turing patterns within growing bacterial populations.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":"15 12","pages":"1105-1106"},"PeriodicalIF":0.0,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866666","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tumor architecture and emergence of strong genetic alterations are bottlenecks for clonal evolution in primary prostate cancer. 肿瘤结构和强基因改变的出现是原发性前列腺癌克隆进化的瓶颈。
Cell systems Pub Date : 2024-11-20 Epub Date: 2024-11-13 DOI: 10.1016/j.cels.2024.10.005
Florian Kreten, Reinhard Büttner, Martin Peifer, Christian Harder, Axel M Hillmer, Nima Abedpour, Anton Bovier, Yuri Tolkach
{"title":"Tumor architecture and emergence of strong genetic alterations are bottlenecks for clonal evolution in primary prostate cancer.","authors":"Florian Kreten, Reinhard Büttner, Martin Peifer, Christian Harder, Axel M Hillmer, Nima Abedpour, Anton Bovier, Yuri Tolkach","doi":"10.1016/j.cels.2024.10.005","DOIUrl":"10.1016/j.cels.2024.10.005","url":null,"abstract":"<p><p>Prostate cancer (PCA) exhibits high levels of intratumoral heterogeneity. In this study, we developed a mathematical model to study the growth and genetic evolution of PCA. We explored the possible evolutionary patterns and demonstrated that tumor architecture represents a major bottleneck for divergent clonal evolution. Early consecutive acquisition of strong genetic alterations serves as a proxy for the formation of aggressive tumors. A limited number of clonal hierarchy patterns were identified. A biopsy study of synthetic tumors shows complex spatial intermixing of clones and delineates the importance of biopsy extent. Deep whole-exome multiregional next-generation DNA sequencing of the primary tumors from five patients was performed to validate the results, supporting our main findings from mathematical modeling. In conclusion, our model provides qualitatively realistic predictions of PCA genomic evolution, closely aligned with the evidence available from patient samples. We share the code of the model for further studies. A record of this paper's transparent peer review process is included in the supplemental information.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"1061-1074.e7"},"PeriodicalIF":0.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Systematic analysis identifies a connection between spatial and genomic variations of chromatin states. 系统分析确定了染色质状态的空间变化与基因组变化之间的联系。
Cell systems Pub Date : 2024-11-20 Epub Date: 2024-11-13 DOI: 10.1016/j.cels.2024.10.006
Xuan Cao, Terry Ma, Rong Fan, Guo-Cheng Yuan
{"title":"Systematic analysis identifies a connection between spatial and genomic variations of chromatin states.","authors":"Xuan Cao, Terry Ma, Rong Fan, Guo-Cheng Yuan","doi":"10.1016/j.cels.2024.10.006","DOIUrl":"10.1016/j.cels.2024.10.006","url":null,"abstract":"<p><p>Chromatin states play important roles in the maintenance of cell identities, yet their spatial patterns remain poorly characterized at the organism scale. We developed a systematic approach to analyzing spatial epigenomic data and then applied it to a recently published spatial-CUT&Tag dataset that was obtained from a mouse embryo. We identified a set of spatial genes whose H3K4me3 patterns delineate tissue boundaries. These genes are enriched with tissue-specific transcription factors, and their corresponding genomic loci are marked by broad H3K4me3 domains. Integrative analysis with H3K27me3 profiles showed coordinated spatial transitions across tissue boundaries, which is marked by the continuous shortening of H3K4me3 domains and expansion of H3K27me3 domains. Motif-based analysis identified transcription factors whose activities change significantly during such transitions. Taken together, our systematic analyses reveal a strong connection between the genomic and spatial variations of chromatin states. A record of this paper's transparent peer review process is included in the supplemental information.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"1092-1102.e2"},"PeriodicalIF":0.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11581903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Systematic screens for fertility genes essential for malaria parasite transmission reveal conserved aspects of sex in a divergent eukaryote. 对疟原虫传播所必需的生育基因进行系统筛选,揭示了真核生物在性方面的保守性。
Cell systems Pub Date : 2024-11-20 Epub Date: 2024-11-13 DOI: 10.1016/j.cels.2024.10.008
Claire Sayers, Vikash Pandey, Arjun Balakrishnan, Katharine Michie, Dennis Svedberg, Mirjam Hunziker, Mercedes Pardo, Jyoti Choudhary, Ronnie Berntsson, Oliver Billker
{"title":"Systematic screens for fertility genes essential for malaria parasite transmission reveal conserved aspects of sex in a divergent eukaryote.","authors":"Claire Sayers, Vikash Pandey, Arjun Balakrishnan, Katharine Michie, Dennis Svedberg, Mirjam Hunziker, Mercedes Pardo, Jyoti Choudhary, Ronnie Berntsson, Oliver Billker","doi":"10.1016/j.cels.2024.10.008","DOIUrl":"10.1016/j.cels.2024.10.008","url":null,"abstract":"<p><p>Sexual reproduction in malaria parasites is essential for their transmission to mosquitoes and offers a divergent eukaryote model to understand the evolution of sex. Through a panel of genetic screens in Plasmodium berghei, we identify 348 sex and transmission-related genes and define roles for unstudied genes as putative targets for transmission-blocking interventions. The functional data provide a deeper understanding of female metabolic reprogramming, meiosis, and the axoneme. We identify a complex of a SUN domain protein (SUN1) and a putative allantoicase (ALLC1) that is essential for male fertility by linking the microtubule organizing center to the nuclear envelope and enabling mitotic spindle formation during male gametogenesis. Both proteins have orthologs in mouse testis, and the data raise the possibility of an ancient role for atypical SUN domain proteins in coupling the nucleus and axoneme. Altogether, our data provide an unbiased picture of the molecular processes that underpin malaria parasite transmission. A record of this paper's transparent peer review process is included in the supplemental information.</p>","PeriodicalId":93929,"journal":{"name":"Cell systems","volume":" ","pages":"1075-1091.e6"},"PeriodicalIF":0.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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