Pub Date : 2024-03-27DOI: 10.1038/s41551-024-01189-4
The mechanical sensor PIEZO1 regulates the traction force that is critical for cytotoxic T cells to target tumour cells. This finding creates avenues for enhancing the efficacy of T cell-targeted immune therapies.
{"title":"Targeting the PIEZO1 pathway boosts T cell antitumour cytotoxicity","authors":"","doi":"10.1038/s41551-024-01189-4","DOIUrl":"10.1038/s41551-024-01189-4","url":null,"abstract":"The mechanical sensor PIEZO1 regulates the traction force that is critical for cytotoxic T cells to target tumour cells. This finding creates avenues for enhancing the efficacy of T cell-targeted immune therapies.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":26.8,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140303830","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 : 2024-03-25DOI: 10.1038/s41551-024-01199-2
Applied biomedical research needs more of them to be more broadly useful, reproducible and robust.
应用生物医学研究需要更多这样的研究成果，才能更广泛地发挥作用，具有可重复性和稳健性。
{"title":"Methods, techniques, assays and protocols","authors":"","doi":"10.1038/s41551-024-01199-2","DOIUrl":"10.1038/s41551-024-01199-2","url":null,"abstract":"Applied biomedical research needs more of them to be more broadly useful, reproducible and robust.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01199-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288622","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}
The killing function of cytotoxic T cells can be enhanced biochemically. Here we show that blocking the mechanical sensor PIEZO1 in T cells strengthens their traction forces and augments their cytotoxicity against tumour cells. By leveraging cytotoxic T cells collected from tumour models in mice and from patients with cancers, we show that PIEZO1 upregulates the transcriptional factor GRHL3, which in turn induces the expression of the E3 ubiquitin ligase RNF114. RNF114 binds to filamentous actin, causing its downregulation and rearrangement, which depresses traction forces in the T cells. In mice with tumours, the injection of cytotoxic T cells collected from the animals and treated with a PIEZO1 antagonist promoted their infiltration into the tumour and attenuated tumour growth. As an immunomechanical regulator, PIEZO1 could be targeted to enhance the outcomes of cancer immunotherapies. Blocking the mechanical sensor PIEZO1 in cytotoxic T lymphocytes strengthens their traction forces and augments their cytotoxicity against tumour cells.
细胞毒性 T 细胞的杀伤功能可以通过生物化学方法得到增强。在这里，我们展示了阻断T细胞中的机械传感器PIEZO1能增强它们的牵引力，提高它们对肿瘤细胞的细胞毒性。通过利用从小鼠肿瘤模型和癌症患者身上收集到的细胞毒性 T 细胞，我们发现 PIEZO1 会上调转录因子 GRHL3，进而诱导 E3 泛素连接酶 RNF114 的表达。RNF114 与丝状肌动蛋白结合，导致其下调和重排，从而抑制了 T 细胞的牵引力。在患有肿瘤的小鼠体内，注射从动物体内收集并经 PIEZO1 拮抗剂处理的细胞毒性 T 细胞，可促进 T 细胞浸润肿瘤并抑制肿瘤生长。作为一种免疫机械调节剂，PIEZO1可以作为靶点来提高癌症免疫疗法的效果。
{"title":"PIEZO1 mechanically regulates the antitumour cytotoxicity of T lymphocytes","authors":"Ruiyang Pang, Weihao Sun, Yingyun Yang, Dahan Wen, Feng Lin, Dingding Wang, Kailong Li, Ning Zhang, Junbo Liang, Chunyang Xiong, Yuying Liu","doi":"10.1038/s41551-024-01188-5","DOIUrl":"10.1038/s41551-024-01188-5","url":null,"abstract":"The killing function of cytotoxic T cells can be enhanced biochemically. Here we show that blocking the mechanical sensor PIEZO1 in T cells strengthens their traction forces and augments their cytotoxicity against tumour cells. By leveraging cytotoxic T cells collected from tumour models in mice and from patients with cancers, we show that PIEZO1 upregulates the transcriptional factor GRHL3, which in turn induces the expression of the E3 ubiquitin ligase RNF114. RNF114 binds to filamentous actin, causing its downregulation and rearrangement, which depresses traction forces in the T cells. In mice with tumours, the injection of cytotoxic T cells collected from the animals and treated with a PIEZO1 antagonist promoted their infiltration into the tumour and attenuated tumour growth. As an immunomechanical regulator, PIEZO1 could be targeted to enhance the outcomes of cancer immunotherapies. Blocking the mechanical sensor PIEZO1 in cytotoxic T lymphocytes strengthens their traction forces and augments their cytotoxicity against tumour cells.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":26.8,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140185014","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}
Oncolytic bacteria can trigger innate immune activity. However, the antitumour efficacy of inactivated bacteria is poor, and attenuated live bacteria pose substantial safety risks. Here we show that intratumourally injected paraformaldehyde-fixed bacteria coated with manganese dioxide potently activate innate immune activity, modulate the immunosuppressive tumour microenvironment and trigger tumour-specific immune responses and abscopal antitumour responses. A single intratumoural administration of mineralized Salmonella typhimurium suppressed the growth of multiple types of subcutaneous and orthotopic tumours in mice, rabbits and tree shrews and protected the cured animals against tumour rechallenge. We also show that mineralized bacteria can be administered via arterial embolization to treat orthotopic liver cancer in rabbits. Our findings support the further translational testing of oncolytic mineralized bacteria as potent and safe antitumour immunotherapeutics. Intratumourally administered bacteria coated with manganese dioxide modulate the immunosuppressive tumour microenvironment and potently activate antitumour immune responses, as shown in multiple solid tumours in small animals.
{"title":"Oncolytic mineralized bacteria as potent locally administered immunotherapeutics","authors":"Chenya Wang, Liping Zhong, Jiachen Xu, Qi Zhuang, Fei Gong, Xiaojing Chen, Huiquan Tao, Cong Hu, Fuquan Huang, Nailin Yang, Junyan Li, Qi Zhao, Xinjun Sun, Yu Huo, Qian Chen, Yongxiang Zhao, Rui Peng, Zhuang Liu","doi":"10.1038/s41551-024-01191-w","DOIUrl":"10.1038/s41551-024-01191-w","url":null,"abstract":"Oncolytic bacteria can trigger innate immune activity. However, the antitumour efficacy of inactivated bacteria is poor, and attenuated live bacteria pose substantial safety risks. Here we show that intratumourally injected paraformaldehyde-fixed bacteria coated with manganese dioxide potently activate innate immune activity, modulate the immunosuppressive tumour microenvironment and trigger tumour-specific immune responses and abscopal antitumour responses. A single intratumoural administration of mineralized Salmonella typhimurium suppressed the growth of multiple types of subcutaneous and orthotopic tumours in mice, rabbits and tree shrews and protected the cured animals against tumour rechallenge. We also show that mineralized bacteria can be administered via arterial embolization to treat orthotopic liver cancer in rabbits. Our findings support the further translational testing of oncolytic mineralized bacteria as potent and safe antitumour immunotherapeutics. Intratumourally administered bacteria coated with manganese dioxide modulate the immunosuppressive tumour microenvironment and potently activate antitumour immune responses, as shown in multiple solid tumours in small animals.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140185013","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 : 2024-03-21DOI: 10.1038/s41551-024-01193-8
Francisco Carrillo-Perez, Marija Pizurica, Yuanning Zheng, Tarak Nath Nandi, Ravi Madduri, Jeanne Shen, Olivier Gevaert
Training machine-learning models with synthetically generated data can alleviate the problem of data scarcity when acquiring diverse and sufficiently large datasets is costly and challenging. Here we show that cascaded diffusion models can be used to synthesize realistic whole-slide image tiles from latent representations of RNA-sequencing data from human tumours. Alterations in gene expression affected the composition of cell types in the generated synthetic image tiles, which accurately preserved the distribution of cell types and maintained the cell fraction observed in bulk RNA-sequencing data, as we show for lung adenocarcinoma, kidney renal papillary cell carcinoma, cervical squamous cell carcinoma, colon adenocarcinoma and glioblastoma. Machine-learning models pretrained with the generated synthetic data performed better than models trained from scratch. Synthetic data may accelerate the development of machine-learning models in scarce-data settings and allow for the imputation of missing data modalities.
{"title":"Generation of synthetic whole-slide image tiles of tumours from RNA-sequencing data via cascaded diffusion models.","authors":"Francisco Carrillo-Perez, Marija Pizurica, Yuanning Zheng, Tarak Nath Nandi, Ravi Madduri, Jeanne Shen, Olivier Gevaert","doi":"10.1038/s41551-024-01193-8","DOIUrl":"10.1038/s41551-024-01193-8","url":null,"abstract":"<p><p>Training machine-learning models with synthetically generated data can alleviate the problem of data scarcity when acquiring diverse and sufficiently large datasets is costly and challenging. Here we show that cascaded diffusion models can be used to synthesize realistic whole-slide image tiles from latent representations of RNA-sequencing data from human tumours. Alterations in gene expression affected the composition of cell types in the generated synthetic image tiles, which accurately preserved the distribution of cell types and maintained the cell fraction observed in bulk RNA-sequencing data, as we show for lung adenocarcinoma, kidney renal papillary cell carcinoma, cervical squamous cell carcinoma, colon adenocarcinoma and glioblastoma. Machine-learning models pretrained with the generated synthetic data performed better than models trained from scratch. Synthetic data may accelerate the development of machine-learning models in scarce-data settings and allow for the imputation of missing data modalities.</p>","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140185012","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 : 2024-03-20DOI: 10.1038/s41551-024-01184-9
CRISPR–Cas12a was used to directly replace mouse antibody variable chain genes with human versions in primary B cells. The edited cells underwent affinity maturation in vivo, improving the potency of HIV-1 and SARS-CoV-2 neutralizing antibodies without loss of bioavailability. Affinity maturation of edited cells also enables new vaccine models and adaptive B cell therapies.
利用CRISPR-Cas12a将原代B细胞中的小鼠抗体可变链基因直接替换为人类版本。经过编辑的细胞在体内进行了亲和性成熟，提高了 HIV-1 和 SARS-CoV-2 中和抗体的效力，同时不损失生物利用度。编辑细胞的亲和性成熟还有助于建立新的疫苗模型和适应性 B 细胞疗法。
{"title":"Affinity maturation of CRISPR-engineered B cell receptors in vivo","authors":"","doi":"10.1038/s41551-024-01184-9","DOIUrl":"10.1038/s41551-024-01184-9","url":null,"abstract":"CRISPR–Cas12a was used to directly replace mouse antibody variable chain genes with human versions in primary B cells. The edited cells underwent affinity maturation in vivo, improving the potency of HIV-1 and SARS-CoV-2 neutralizing antibodies without loss of bioavailability. Affinity maturation of edited cells also enables new vaccine models and adaptive B cell therapies.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140164695","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 : 2024-03-18DOI: 10.1038/s41551-024-01187-6
Noe Brasier, Juliane R. Sempionatto, Steven Bourke, George Havenith, Dietmar Schaffarczyk, Jörg Goldhahn, Christian Lüscher, Wei Gao
A patient-centred system that leverages the analysis of sweat via wearable sensors may better support the management of patients with substance-use disorders.
以患者为中心的系统可利用可穿戴传感器对汗液进行分析，从而为药物滥用障碍患者的管理提供更好的支持。
{"title":"Towards on-skin analysis of sweat for managing disorders of substance abuse","authors":"Noe Brasier, Juliane R. Sempionatto, Steven Bourke, George Havenith, Dietmar Schaffarczyk, Jörg Goldhahn, Christian Lüscher, Wei Gao","doi":"10.1038/s41551-024-01187-6","DOIUrl":"10.1038/s41551-024-01187-6","url":null,"abstract":"A patient-centred system that leverages the analysis of sweat via wearable sensors may better support the management of patients with substance-use disorders.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":26.8,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140146033","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 : 2024-03-18DOI: 10.1038/s41551-024-01183-w
Surabhi R. Madhvapathy, Matthew I. Bury, Larry W. Wang, Joanna L. Ciatti, Raudel Avila, Yonggang Huang, Arun K. Sharma, John A. Rogers
Diagnosing and monitoring inflammatory bowel diseases, such as Crohn’s disease, involves the use of endoscopic imaging, biopsies and serology. These infrequent tests cannot, however, identify sudden onsets and severe flare-ups to facilitate early intervention. Hence, about 70% of patients with Crohn’s disease require surgical intestinal resections in their lifetime. Here we report wireless, miniaturized and implantable temperature sensors for the real-time chronic monitoring of disease progression, which we tested for nearly 4 months in a mouse model of Crohn’s-disease-like ileitis. Local measurements of intestinal temperature via intraperitoneally implanted sensors held in place against abdominal muscular tissue via two sutures showed the development of ultradian rhythms at approximately 5 weeks before the visual emergence of inflammatory skip lesions. The ultradian rhythms showed correlations with variations in the concentrations of stress hormones and inflammatory cytokines in blood. Decreasing average temperatures over the span of approximately 23 weeks were accompanied by an increasing percentage of inflammatory species in ileal lesions. These miniaturized temperature sensors may aid the early treatment of inflammatory bowel diseases upon the detection of episodic flare-ups. Wireless miniaturized implantable temperature sensors enable real-time monitoring of the progression of inflammatory bowel diseases, as shown in a mouse model of Crohn’s-disease-like ileitis.
{"title":"Miniaturized implantable temperature sensors for the long-term monitoring of chronic intestinal inflammation","authors":"Surabhi R. Madhvapathy, Matthew I. Bury, Larry W. Wang, Joanna L. Ciatti, Raudel Avila, Yonggang Huang, Arun K. Sharma, John A. Rogers","doi":"10.1038/s41551-024-01183-w","DOIUrl":"10.1038/s41551-024-01183-w","url":null,"abstract":"Diagnosing and monitoring inflammatory bowel diseases, such as Crohn’s disease, involves the use of endoscopic imaging, biopsies and serology. These infrequent tests cannot, however, identify sudden onsets and severe flare-ups to facilitate early intervention. Hence, about 70% of patients with Crohn’s disease require surgical intestinal resections in their lifetime. Here we report wireless, miniaturized and implantable temperature sensors for the real-time chronic monitoring of disease progression, which we tested for nearly 4 months in a mouse model of Crohn’s-disease-like ileitis. Local measurements of intestinal temperature via intraperitoneally implanted sensors held in place against abdominal muscular tissue via two sutures showed the development of ultradian rhythms at approximately 5 weeks before the visual emergence of inflammatory skip lesions. The ultradian rhythms showed correlations with variations in the concentrations of stress hormones and inflammatory cytokines in blood. Decreasing average temperatures over the span of approximately 23 weeks were accompanied by an increasing percentage of inflammatory species in ileal lesions. These miniaturized temperature sensors may aid the early treatment of inflammatory bowel diseases upon the detection of episodic flare-ups. Wireless miniaturized implantable temperature sensors enable real-time monitoring of the progression of inflammatory bowel diseases, as shown in a mouse model of Crohn’s-disease-like ileitis.","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":26.8,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140145981","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 : 2024-03-15DOI: 10.1038/s41551-024-01198-3
Ningqiang Gong, Xuexiang Han, Lulu Xue, Margaret M. Billingsley, Xisha Huang, Rakan El-Mayta, Jingya Qin, Neil C. Sheppard, Carl H. June, Michael J. Mitchell
{"title":"Author Correction: Small-molecule-mediated control of the anti-tumour activity and off-tumour toxicity of a supramolecular bispecific T cell engager","authors":"Ningqiang Gong, Xuexiang Han, Lulu Xue, Margaret M. Billingsley, Xisha Huang, Rakan El-Mayta, Jingya Qin, Neil C. Sheppard, Carl H. June, Michael J. Mitchell","doi":"10.1038/s41551-024-01198-3","DOIUrl":"10.1038/s41551-024-01198-3","url":null,"abstract":"","PeriodicalId":19063,"journal":{"name":"Nature Biomedical Engineering","volume":null,"pages":null},"PeriodicalIF":28.1,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41551-024-01198-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140140490","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}
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