Pub Date : 2024-10-28DOI: 10.1038/s41551-024-01262-y
Xiao Wang, Youkui Huang, Ling-Ling Chen
Optimized methods for the synthesis of circular RNA in vitro and in cells, and a complementary Cas9 de-immunization method, enhance RNA persistence and reduce immunogenicity for applications in genome engineering and cell engineering.
{"title":"Expanded toolkits for RNA circularization","authors":"Xiao Wang, Youkui Huang, Ling-Ling Chen","doi":"10.1038/s41551-024-01262-y","DOIUrl":"10.1038/s41551-024-01262-y","url":null,"abstract":"Optimized methods for the synthesis of circular RNA in vitro and in cells, and a complementary Cas9 de-immunization method, enhance RNA persistence and reduce immunogenicity for applications in genome engineering and cell engineering.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"9 1","pages":"5-6"},"PeriodicalIF":26.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142519259","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 : 2024-10-25DOI: 10.1038/s41551-024-01270-y
X. Luís Deán-Ben
The quality of three-dimensional optoacoustic images of subcutaneous microvasculature in patients can be enhanced by reducing the scan times of all-optical Fabry–Pérot scanners to a few seconds.
通过将全光学法布里-佩罗扫描仪的扫描时间缩短至几秒钟，可提高患者皮下微血管的三维光声图像质量。
{"title":"All-optical optoacoustics for clinical diagnostics","authors":"X. Luís Deán-Ben","doi":"10.1038/s41551-024-01270-y","DOIUrl":"https://doi.org/10.1038/s41551-024-01270-y","url":null,"abstract":"The quality of three-dimensional optoacoustic images of subcutaneous microvasculature in patients can be enhanced by reducing the scan times of all-optical Fabry–Pérot scanners to a few seconds.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"1 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489207","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 : 2024-10-25DOI: 10.1038/s41551-024-01272-w
Zeyang Liu, Yan-Ruide Li, Youcheng Yang, Yu Zhu, Weihao Yuan, Tyler Hoffman, Yifan Wu, Enbo Zhu, Jana Zarubova, Jun Shen, Haochen Nan, Kun-Wei Yeh, Mohammad Mahdi Hasani-Sadrabadi, Yichen Zhu, Ying Fang, Xinyang Ge, Zhizhong Li, Jennifer Soto, Tzung Hsiai, Lili Yang, Song Li
The use of synthetic antigen-presenting cells to activate and expand engineered T cells for the treatment of cancers typically results in therapies that are suboptimal in effectiveness and durability. Here we describe a high-throughput microfluidic system for the fabrication of synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells. Compared with rigid or elastic microspheres, the synthetic viscoelastic T-cell-activating cells (SynVACs) led to substantial enhancements in the expansion of human CD8+ T cells and to the suppression of the formation of regulatory T cells. Notably, activating and expanding chimaeric antigen receptor (CAR) T cells with SynVACs led to a CAR-transduction efficiency of approximately 90% and to substantial increases in T memory stem cells. The engineered CAR T cells eliminated tumour cells in a mouse model of human lymphoma, suppressed tumour growth in mice with human ovarian cancer xenografts, persisted for longer periods and reduced tumour-recurrence risk. Our findings underscore the crucial roles of viscoelasticity in T-cell engineering and highlight the utility of SynVACs in cancer therapy. Synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells provide substantial enhancements in the expansion and potency of engineered human cytotoxic T cells.
使用合成抗原递呈细胞激活和扩增工程 T 细胞来治疗癌症，通常会导致治疗效果和持久性不理想。在这里，我们描述了一种高通量微流体系统，用于制造模拟抗原递呈细胞粘弹性和 T 细胞激活特性的合成细胞。与刚性或弹性微球相比，合成粘弹性T细胞激活细胞（SynVACs）大大提高了人类CD8+ T细胞的扩增能力，并抑制了调节性T细胞的形成。值得注意的是，用SynVACs激活和扩增奇异抗原受体（CAR）T细胞，可使CAR转导效率达到约90%，并大幅增加T记忆干细胞。经改造的CAR T细胞能消灭人类淋巴瘤小鼠模型中的肿瘤细胞，抑制人类卵巢癌异种移植小鼠的肿瘤生长，延长肿瘤存活时间，降低肿瘤复发风险。我们的研究结果强调了粘弹性在T细胞工程中的关键作用，并突出了SynVACs在癌症治疗中的实用性。
{"title":"Viscoelastic synthetic antigen-presenting cells for augmenting the potency of cancer therapies","authors":"Zeyang Liu, Yan-Ruide Li, Youcheng Yang, Yu Zhu, Weihao Yuan, Tyler Hoffman, Yifan Wu, Enbo Zhu, Jana Zarubova, Jun Shen, Haochen Nan, Kun-Wei Yeh, Mohammad Mahdi Hasani-Sadrabadi, Yichen Zhu, Ying Fang, Xinyang Ge, Zhizhong Li, Jennifer Soto, Tzung Hsiai, Lili Yang, Song Li","doi":"10.1038/s41551-024-01272-w","DOIUrl":"10.1038/s41551-024-01272-w","url":null,"abstract":"The use of synthetic antigen-presenting cells to activate and expand engineered T cells for the treatment of cancers typically results in therapies that are suboptimal in effectiveness and durability. Here we describe a high-throughput microfluidic system for the fabrication of synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells. Compared with rigid or elastic microspheres, the synthetic viscoelastic T-cell-activating cells (SynVACs) led to substantial enhancements in the expansion of human CD8+ T cells and to the suppression of the formation of regulatory T cells. Notably, activating and expanding chimaeric antigen receptor (CAR) T cells with SynVACs led to a CAR-transduction efficiency of approximately 90% and to substantial increases in T memory stem cells. The engineered CAR T cells eliminated tumour cells in a mouse model of human lymphoma, suppressed tumour growth in mice with human ovarian cancer xenografts, persisted for longer periods and reduced tumour-recurrence risk. Our findings underscore the crucial roles of viscoelasticity in T-cell engineering and highlight the utility of SynVACs in cancer therapy. Synthetic cells mimicking the viscoelastic and T-cell-activation properties of antigen-presenting cells provide substantial enhancements in the expansion and potency of engineered human cytotoxic T cells.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 12","pages":"1615-1633"},"PeriodicalIF":26.8,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489208","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 : 2024-10-24DOI: 10.1038/s41551-024-01263-x
We computationally designed protein binders for chimeric antigen receptor (CAR) constructs to target the glioblastoma-associated antigens EGFR and CD276. Compared with standard CAR T cells, CAR T cells with the de novo-designed binders showed enhanced proliferation, cytokine release and resistance to exhaustion, as well as superior antitumour effects in vitro and in vivo.
{"title":"Computational design of protein binders that boost the antitumour efficacy of CAR T cells","authors":"","doi":"10.1038/s41551-024-01263-x","DOIUrl":"10.1038/s41551-024-01263-x","url":null,"abstract":"We computationally designed protein binders for chimeric antigen receptor (CAR) constructs to target the glioblastoma-associated antigens EGFR and CD276. Compared with standard CAR T cells, CAR T cells with the de novo-designed binders showed enhanced proliferation, cytokine release and resistance to exhaustion, as well as superior antitumour effects in vitro and in vivo.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 12","pages":"1521-1522"},"PeriodicalIF":26.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142488424","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 : 2024-10-23DOI: 10.1038/s41551-024-01265-9
Preeti Sharma, Dor Breier, Dan Peer
Amine headgroups in the ionizable lipids of lipid nanoparticles contribute to their immunogenicity.
脂质纳米粒子的可离子化脂质中的胺头基团会增加其免疫原性。
{"title":"Immunogenic amines on lipid nanoparticles","authors":"Preeti Sharma, Dor Breier, Dan Peer","doi":"10.1038/s41551-024-01265-9","DOIUrl":"10.1038/s41551-024-01265-9","url":null,"abstract":"Amine headgroups in the ionizable lipids of lipid nanoparticles contribute to their immunogenicity.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 11","pages":"1332-1333"},"PeriodicalIF":26.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487094","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 : 2024-10-21DOI: 10.1038/s41551-024-01264-w
Fei Wang, Ran Li, Jing Yi Xu, Xiaoxia Bai, Ying Wang, Xu Ri Chen, Chen Pan, Shen Chen, Ke Zhou, Boon Chin Heng, Xuewei Wu, Wei Guo, Zhe Song, Shu Cheng Jin, Jing Zhou, Xiao Hui Zou, Hong Wei Ouyang, Hua Liu
Immune rejection caused by mismatches in human leucocyte antigens (HLAs) remains a major obstacle to the success of allogeneic cell therapies. Current strategies for the generation of ‘universal’ immune-compatible cells, particularly the editing of HLA class I (HLA-I) genes or the modulation of proteins that inhibit natural killer cells, often result in genomic instability or cellular cytotoxicity. Here we show that a β2-microglobulin super-enhancer (B2M-SE) that is responsive to interferon-γ is a critical regulator of the expression of HLA-I on mesenchymal stromal cells (MSCs). Targeted epigenetic repression of B2M-SE in MSCs reduced the surface expression of HLA-I below the threshold required to activate allogenic T cells while maintaining levels sufficient to evade cytotoxicity mediated by natural killer cells. In a humanized mouse model, the epigenetically edited MSCs demonstrated improved survival by evading the immune system, allowing them to exert enhanced therapeutic effects on LPS-induced acute lung injury. Targeted epigenetic repression of B2M-SE may facilitate the development of off-the-shelf cell sources for allogeneic cell therapy. The targeted epigenetic repression of a β2-microglobulin super-enhancer downregulates the expression of human leucocyte antigens on mesenchymal stromal cells, making the cells suitable for allogeneic cell therapy.
人类白细胞抗原（HLA）不匹配引起的免疫排斥仍是异体细胞疗法取得成功的主要障碍。目前生成 "通用 "免疫相容细胞的策略，特别是编辑 HLA I 类（HLA-I）基因或调节抑制自然杀伤细胞的蛋白质，往往会导致基因组不稳定或细胞毒性。在这里，我们发现对干扰素-γ有反应的β2-微球蛋白超级增强子（B2M-SE）是间充质基质细胞（MSCs）上HLA-I表达的关键调节因子。间充质干细胞中 B2M-SE 的靶向表观遗传抑制可将 HLA-I 的表面表达降低到激活异源 T 细胞所需的阈值以下，同时保持足够的水平以规避自然杀伤细胞介导的细胞毒性。在人源化小鼠模型中，经过表观遗传学编辑的间充质干细胞通过逃避免疫系统而提高了存活率，从而使它们对 LPS 诱导的急性肺损伤发挥了更强的治疗效果。对B2M-SE进行靶向表观遗传学抑制可能有助于开发用于异体细胞治疗的现成细胞来源。
{"title":"Downregulating human leucocyte antigens on mesenchymal stromal cells by epigenetically repressing a β2-microglobulin super-enhancer","authors":"Fei Wang, Ran Li, Jing Yi Xu, Xiaoxia Bai, Ying Wang, Xu Ri Chen, Chen Pan, Shen Chen, Ke Zhou, Boon Chin Heng, Xuewei Wu, Wei Guo, Zhe Song, Shu Cheng Jin, Jing Zhou, Xiao Hui Zou, Hong Wei Ouyang, Hua Liu","doi":"10.1038/s41551-024-01264-w","DOIUrl":"10.1038/s41551-024-01264-w","url":null,"abstract":"Immune rejection caused by mismatches in human leucocyte antigens (HLAs) remains a major obstacle to the success of allogeneic cell therapies. Current strategies for the generation of ‘universal’ immune-compatible cells, particularly the editing of HLA class I (HLA-I) genes or the modulation of proteins that inhibit natural killer cells, often result in genomic instability or cellular cytotoxicity. Here we show that a β2-microglobulin super-enhancer (B2M-SE) that is responsive to interferon-γ is a critical regulator of the expression of HLA-I on mesenchymal stromal cells (MSCs). Targeted epigenetic repression of B2M-SE in MSCs reduced the surface expression of HLA-I below the threshold required to activate allogenic T cells while maintaining levels sufficient to evade cytotoxicity mediated by natural killer cells. In a humanized mouse model, the epigenetically edited MSCs demonstrated improved survival by evading the immune system, allowing them to exert enhanced therapeutic effects on LPS-induced acute lung injury. Targeted epigenetic repression of B2M-SE may facilitate the development of off-the-shelf cell sources for allogeneic cell therapy. The targeted epigenetic repression of a β2-microglobulin super-enhancer downregulates the expression of human leucocyte antigens on mesenchymal stromal cells, making the cells suitable for allogeneic cell therapy.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 12","pages":"1682-1699"},"PeriodicalIF":26.8,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451816","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 : 2024-10-17DOI: 10.1038/s41551-024-01276-6
The design of implanted biomaterials and devices should involve strategies for the prevention of inflammation and fibrosis that enhance the functional lifespan of the implants.
植入式生物材料和设备的设计应包括预防炎症和纤维化的策略，以延长植入物的功能寿命。
{"title":"Overcoming immune hurdles to implant longevity","authors":"","doi":"10.1038/s41551-024-01276-6","DOIUrl":"10.1038/s41551-024-01276-6","url":null,"abstract":"The design of implanted biomaterials and devices should involve strategies for the prevention of inflammation and fibrosis that enhance the functional lifespan of the implants.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 10","pages":"1191-1192"},"PeriodicalIF":26.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01276-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447858","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 : 2024-10-17DOI: 10.1038/s41551-024-01266-8
Julia Garcia Mancebo, Kristen Sack, Jay Hartford, Saffron Dominguez, Michelle Balcarcel-Monzon, Elizabeth Chartier, Tien Nguyen, Alexis R. Cole, Francesca Sperotto, David M. Harrild, Brian D. Polizzotti, Allen D. Everett, Alan B. Packard, Jason Dearling, Arthur G. Nedder, Simon Warfield, Edward Yang, Hart G. W. Lidov, John N. Kheir, Yifeng Peng
Acute respiratory failure can cause profound hypoxaemia that leads to organ injury or death within minutes. When conventional interventions are ineffective, the intravenous administration of oxygen can rescue patients from severe hypoxaemia, but at the risk of microvascular obstruction and of toxicity of the carrier material. Here we describe polymeric microbubbles as carriers of high volumes of oxygen (350–500 ml of oxygen per litre of foam) that are stable in storage yet quickly dissolve following intravenous injection, reverting to their soluble and excretable molecular constituents. In swine with profound hypoxaemia owing to acute and temporary (12 min) upper-airway obstruction, the microbubble-mediated delivery of oxygen led to: the maintenance of critical oxygenation, lowered burdens of cardiac arrest, improved survival, and substantially improved neurologic and kidney function in surviving animals. Our findings underscore the importance of maintaining a critical threshold of oxygenation and the promise of injectable oxygen as a viable therapy in acute and temporary hypoxaemic crises. The intravenous injection of oxygen via polymeric microbubbles that are stable in storage yet quickly dissolve following intravenous injection led to the maintenance of critical oxygenation and to improved survival in swine with profound hypoxaemia.
{"title":"Systemically injected oxygen within rapidly dissolving microbubbles improves the outcomes of severe hypoxaemia in swine","authors":"Julia Garcia Mancebo, Kristen Sack, Jay Hartford, Saffron Dominguez, Michelle Balcarcel-Monzon, Elizabeth Chartier, Tien Nguyen, Alexis R. Cole, Francesca Sperotto, David M. Harrild, Brian D. Polizzotti, Allen D. Everett, Alan B. Packard, Jason Dearling, Arthur G. Nedder, Simon Warfield, Edward Yang, Hart G. W. Lidov, John N. Kheir, Yifeng Peng","doi":"10.1038/s41551-024-01266-8","DOIUrl":"10.1038/s41551-024-01266-8","url":null,"abstract":"Acute respiratory failure can cause profound hypoxaemia that leads to organ injury or death within minutes. When conventional interventions are ineffective, the intravenous administration of oxygen can rescue patients from severe hypoxaemia, but at the risk of microvascular obstruction and of toxicity of the carrier material. Here we describe polymeric microbubbles as carriers of high volumes of oxygen (350–500 ml of oxygen per litre of foam) that are stable in storage yet quickly dissolve following intravenous injection, reverting to their soluble and excretable molecular constituents. In swine with profound hypoxaemia owing to acute and temporary (12 min) upper-airway obstruction, the microbubble-mediated delivery of oxygen led to: the maintenance of critical oxygenation, lowered burdens of cardiac arrest, improved survival, and substantially improved neurologic and kidney function in surviving animals. Our findings underscore the importance of maintaining a critical threshold of oxygenation and the promise of injectable oxygen as a viable therapy in acute and temporary hypoxaemic crises. The intravenous injection of oxygen via polymeric microbubbles that are stable in storage yet quickly dissolve following intravenous injection led to the maintenance of critical oxygenation and to improved survival in swine with profound hypoxaemia.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 11","pages":"1396-1411"},"PeriodicalIF":26.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01266-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440824","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}
Chimeric antigen receptor (CAR) T cells targeting receptors on tumour cells have had limited success in patients with glioblastoma. Here we report the development and therapeutic performance of CAR constructs leveraging protein binders computationally designed de novo to have high affinity for the epidermal growth factor receptor (EGFR) or the tumour-associated antigen CD276, which are overexpressed in glioblastoma. With respect to T cells with a CAR using an antibody-derived single-chain variable fragment as antigen-binding domain, the designed binders on CAR T cells promoted the proliferation of the cells, the secretion of cytotoxic cytokines and their resistance to cell exhaustion, and improved antitumour performance in vitro and in vivo. Moreover, CARs with the binders exhibited higher surface expression and greater resistance to degradation, as indicated by bulk and single-cell transcriptional profiling of the cells. The de novo design of binding domains for specific tumour antigens may potentiate the antitumour efficacy of CAR T cell therapies for other solid cancers. Computationally designed protein binders with high affinity for overexpressed antigens on tumour cells in glioblastoma enhance the antitumour activity of cytotoxic T cells with chimeric antigen receptors.
以肿瘤细胞上的受体为靶点的嵌合抗原受体（CAR）T细胞在胶质母细胞瘤患者中的疗效有限。在这里，我们报告了利用通过计算重新设计的蛋白结合体的 CAR 构建物的开发和治疗效果，这种结合体对表皮生长因子受体（EGFR）或肿瘤相关抗原 CD276 具有高亲和力，而表皮生长因子受体或肿瘤相关抗原 CD276 在胶质母细胞瘤中过度表达。对于使用抗体衍生的单链可变片段作为抗原结合域的CAR T细胞，CAR T细胞上设计的结合剂促进了细胞的增殖、细胞毒性细胞因子的分泌和细胞衰竭的抵抗力，并提高了体外和体内的抗肿瘤性能。此外，细胞的大量和单细胞转录谱分析表明，带有结合域的 CAR 具有更高的表面表达能力和更强的抗降解能力。重新设计特定肿瘤抗原的结合域可能会增强CAR T细胞疗法对其他实体瘤的抗肿瘤疗效。
{"title":"Targeting overexpressed antigens in glioblastoma via CAR T cells with computationally designed high-affinity protein binders","authors":"Zhen Xia, Qihan Jin, Zhilin Long, Yexuan He, Fuyi Liu, Chengfang Sun, Jinyang Liao, Chun Wang, Chentong Wang, Jian Zheng, Weixi Zhao, Tianxin Zhang, Jeremy N. Rich, Yongdeng Zhang, Longxing Cao, Qi Xie","doi":"10.1038/s41551-024-01258-8","DOIUrl":"10.1038/s41551-024-01258-8","url":null,"abstract":"Chimeric antigen receptor (CAR) T cells targeting receptors on tumour cells have had limited success in patients with glioblastoma. Here we report the development and therapeutic performance of CAR constructs leveraging protein binders computationally designed de novo to have high affinity for the epidermal growth factor receptor (EGFR) or the tumour-associated antigen CD276, which are overexpressed in glioblastoma. With respect to T cells with a CAR using an antibody-derived single-chain variable fragment as antigen-binding domain, the designed binders on CAR T cells promoted the proliferation of the cells, the secretion of cytotoxic cytokines and their resistance to cell exhaustion, and improved antitumour performance in vitro and in vivo. Moreover, CARs with the binders exhibited higher surface expression and greater resistance to degradation, as indicated by bulk and single-cell transcriptional profiling of the cells. The de novo design of binding domains for specific tumour antigens may potentiate the antitumour efficacy of CAR T cell therapies for other solid cancers. Computationally designed protein binders with high affinity for overexpressed antigens on tumour cells in glioblastoma enhance the antitumour activity of cytotoxic T cells with chimeric antigen receptors.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"8 12","pages":"1634-1650"},"PeriodicalIF":26.8,"publicationDate":"2024-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440823","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 : 2024-10-15DOI: 10.1038/s41551-024-01268-6
Rui Yan, Md Tauhidual Islam, Lei Xing
Tabular data—rows of samples and columns of sample features—are ubiquitously used across disciplines. Yet the tabular representation makes it difficult to discover underlying associations in the data and thus hinders their analysis and the discovery of useful patterns. Here we report a broadly applicable strategy for unravelling intertwined relationships in tabular data by reconfiguring each data sample into a spatially semantic 2D topographic map, which we refer to as TabMap. A TabMap preserves the original feature values as pixel intensities, with the relationships among the features spatially encoded in the map (the strength of two inter-related features correlates with their distance on the map). TabMap makes it possible to apply 2D convolutional neural networks to extract association patterns in the data to aid data analysis, and offers interpretability by ranking features according to importance. We show the superior predictive performance of TabMap by applying it to 12 datasets across a wide range of biomedical applications, including disease diagnosis, human activity recognition, microbial identification and the analysis of quantitative structure–activity relationships.
{"title":"Interpretable discovery of patterns in tabular data via spatially semantic topographic maps","authors":"Rui Yan, Md Tauhidual Islam, Lei Xing","doi":"10.1038/s41551-024-01268-6","DOIUrl":"https://doi.org/10.1038/s41551-024-01268-6","url":null,"abstract":"<p>Tabular data—rows of samples and columns of sample features—are ubiquitously used across disciplines. Yet the tabular representation makes it difficult to discover underlying associations in the data and thus hinders their analysis and the discovery of useful patterns. Here we report a broadly applicable strategy for unravelling intertwined relationships in tabular data by reconfiguring each data sample into a spatially semantic 2D topographic map, which we refer to as TabMap. A TabMap preserves the original feature values as pixel intensities, with the relationships among the features spatially encoded in the map (the strength of two inter-related features correlates with their distance on the map). TabMap makes it possible to apply 2D convolutional neural networks to extract association patterns in the data to aid data analysis, and offers interpretability by ranking features according to importance. We show the superior predictive performance of TabMap by applying it to 12 datasets across a wide range of biomedical applications, including disease diagnosis, human activity recognition, microbial identification and the analysis of quantitative structure–activity relationships.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":"64 1","pages":""},"PeriodicalIF":28.1,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436341","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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