Nature cancer最新文献

{"title":"Deciphering the response to BCMA CAR T cell therapy","authors":"Hamza Hassan, Marco L. Davila","doi":"10.1038/s43018-024-00826-w","DOIUrl":"10.1038/s43018-024-00826-w","url":null,"abstract":"Despite the promise of chimeric antigen receptor (CAR) T cell therapy, predicting patient response is challenging. Single-cell multiomics of myeloma treated with B cell maturation antigen (BCMA)-targeted CAR T cells now reveal that poor clinical response is associated with an immunosuppressive environment and CAR T cells transition to exhausted phenotypes, indicating a mechanism for reduced persistence.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 9","pages":"1287-1288"},"PeriodicalIF":23.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253738","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":"Vascular heterogeneity of tight junction Claudins guides organotropic metastasis","authors":"Xunian Zhou, Valerie S. LeBleu, Eliot Fletcher-Sananikone, Jiha Kim, Jianli Dai, Bingrui Li, Chia-Chin Wu, Hikaru Sugimoto, Toru Miyake, Lisa M. Becker, Olga V. Volpert, Erica Lawson, Cristina Espinosa Da Silva, Sarah I. Patel, Akane Kizu, Ehsan A. Ehsanipour, Di Sha, Jose Antonio Karam, Kathleen M. McAndrews, Raghu Kalluri","doi":"10.1038/s43018-024-00813-1","DOIUrl":"10.1038/s43018-024-00813-1","url":null,"abstract":"Carcinomas are associated with metastasis to specific organs while sparing others. Breast cancer presents with lung metastasis but rarely kidney metastasis. Using this difference as an example, we queried the mechanism(s) behind the proclivity for organ-specific metastasis. We used spontaneous and implant models of metastatic mammary carcinoma coupled with inflammatory tissue fibrosis, single-cell sequencing analyses and functional studies to unravel the causal determinants of organ-specific metastasis. Here we show that lung metastasis is facilitated by angiopoietin 2 (Ang2)-mediated suppression of lung-specific endothelial tight junction protein Claudin 5, which is augmented by the inflammatory fibrotic microenvironment and prevented by anti-Ang2 blocking antibodies, while kidney metastasis is prevented by non-Ang2-responsive Claudins 2 and 10. Suppression of Claudins 2 and 10 was sufficient to induce the emergence of kidney metastasis. This study illustrates the influence of organ-specific vascular heterogeneity in determining organotropic metastasis, independent of cancer cell-intrinsic mechanisms. Kalluri and colleagues use mammary carcinoma models to study the causes of metastatic organotropism and find an organ-specific role for angiopoietin 2 in driving lung metastasis through the suppression of the tight junction protein Claudin 5.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 9","pages":"1371-1389"},"PeriodicalIF":23.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253741","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 therapy-persistent residual disease","authors":"Xiaoxiao Sun, Lani F. Wu, Steven J. Altschuler, Aaron N. Hata","doi":"10.1038/s43018-024-00819-9","DOIUrl":"10.1038/s43018-024-00819-9","url":null,"abstract":"Disease relapse driven by acquired drug resistance limits the effectiveness of most systemic anti-cancer agents. Targeting persistent cancer cells in residual disease before relapse has emerged as a potential strategy for enhancing the efficacy and the durability of current therapies. However, barriers remain to implementing persister-directed approaches in the clinic. This Perspective discusses current preclinical and clinical complexities and outlines key steps toward the development of clinical strategies that target therapy-persistent residual disease. Hata and colleagues discuss the complexity and clinical importance of cancer persister cells, as well as existing methods for studying and eliminating them, expanding on challenges and opportunities in this area of research.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 9","pages":"1298-1304"},"PeriodicalIF":23.5,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253740","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":"ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells","authors":"Laura Carretero-Iglesia, Olivia J. Hall, Jérémy Berret, Daniela Pais, Carole Estoppey, Myriam Chimen, Thierry Monney, Jeremy Loyau, Cyrille Dreyfus, Julie Macoin, Cynthia Perez, Vinu Menon, Isabelle Gruber, Amélie Laurendon, Lydia N. Caro, Girish S. Gudi, Tomomi Matsuura, Piet H. van der Graaf, Stanislas Blein, M. Lamine Mbow, Rebecca Croasdale-Wood, Ankita Srivastava, Michael R. Dyson, Thomas Matthes, Zeynep Kaya, Claire M. Edwards, James R. Edwards, Sophie Maiga, Catherine Pellat-Deceunynck, Cyrille Touzeau, Philippe Moreau, Cyril Konto, Adam Drake, Eugene A. Zhukovsky, Mario Perro, Maria Pihlgren","doi":"10.1038/s43018-024-00821-1","DOIUrl":"10.1038/s43018-024-00821-1","url":null,"abstract":"Despite recent advances in immunotherapies targeting single tumor-associated antigens, patients with multiple myeloma eventually relapse. ISB 2001 is a CD3+ T cell engager (TCE) co-targeting BCMA and CD38 designed to improve cytotoxicity against multiple myeloma. Targeting of two tumor-associated antigens by a single TCE resulted in superior cytotoxic potency across a variable range of BCMA and CD38 tumor expression profiles mimicking natural tumor heterogeneity, improved resistance to competing soluble factors and exhibited superior cytotoxic potency on patient-derived samples and in mouse models. Despite the broad expression of CD38 across human tissues, ISB 2001 demonstrated a reduced T cell activation profile in the absence of tumor cells when compared to TCEs targeting CD38 only. To determine an optimal first-in-human dose for the ongoing clinical trial ( NCT05862012 ), we developed an innovative quantitative systems pharmacology model leveraging preclinical data, using a minimum pharmacologically active dose approach, therefore reducing patient exposure to subefficacious doses of therapies. Perro and colleagues develop a CD3+ T cell engager co-targeting BCMA and CD38 to improve immunotherapy for multiple myeloma, demonstrate cytotoxicity in patient-derived samples and murine models and develop a quantitative systems pharmacology model.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1494-1514"},"PeriodicalIF":23.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00821-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175804","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":"MCL1 inhibitor BRD-810 kills cancer cells while minimizing risk of cardiotoxicity","authors":"","doi":"10.1038/s43018-024-00815-z","DOIUrl":"10.1038/s43018-024-00815-z","url":null,"abstract":"The anti-apoptotic protein MCL1 is a therapeutic target in cancer, but long-term MCL1 inhibition has been found to increase the risk of cardiotoxicity. We developed BRD-810 as a potent and selective MCL1 inhibitor that induces cancer cell death in vivo within a few hours. As BRD-810 was designed to be rapidly cleared, it targets cancer cells while minimizing the risk for cardiotoxicity.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1457-1458"},"PeriodicalIF":23.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175802","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":"Antibody avidity meets multiple myeloma","authors":"Sigrid R. Ruuls, Paul W. H. I. Parren","doi":"10.1038/s43018-024-00805-1","DOIUrl":"10.1038/s43018-024-00805-1","url":null,"abstract":"In the ongoing search for innovative treatments to combat refractory and relapsed cancer, new preclinical work in multiple myeloma shows that increasing binding avidity by targeting two antigens in one T cell-engaging trispecific antibody boosts anti-tumor activity and reduces the likelihood of tumor escape relative to current antibody-based therapies.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1452-1454"},"PeriodicalIF":23.5,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175801","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":"Neoadjuvant gemcitabine–cisplatin plus tislelizumab in persons with resectable muscle-invasive bladder cancer: a multicenter, single-arm, phase 2 trial","authors":"Kaiwen Li, Wenlong Zhong, Jinhai Fan, Shaogang Wang, Dexin Yu, Tao Xu, Jiaju Lyu, Shaoxu Wu, Tao Qin, Zhuo Wu, Longhao Xu, Kaijie Wu, Zheng Liu, Zhiquan Hu, Fan Li, Jinyou Wang, Qi Wang, Jie Min, Zhiqiang Zhang, Luping Yu, Sentai Ding, Longfei Huang, Tingting Zhao, Jian Huang, Tianxin Lin","doi":"10.1038/s43018-024-00822-0","DOIUrl":"10.1038/s43018-024-00822-0","url":null,"abstract":"Programmed death 1 blockade (tislelizumab) has been approved for metastatic urothelial carcinoma but not as part of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC). In this multicenter single-arm trial (ChiCTR2000037670), 65 participants with cT2-4aN0M0 MIBC received neoadjuvant gemcitabine–cisplatin plus tislelizumab; 57 of them underwent radical cystectomy (RC). The primary endpoint of pathologic complete response (pCR) rate was 50.9% (29/57, 95% confidence interval (CI) 37.3–64.4%) and the pathologic downstaging (secondary endpoint) rate was 75.4% (43/57, 95% CI 62.2–85.9%) in participants undergoing RC. Genomic and transcriptomic analyses revealed three MIBC molecular subtypes (S): S1 (immune-desert) with activated cell-cycle pathway, S2 (immune-excluded) with activated transforming growth factor-β pathway and S3 (immune-inflamed) with upregulated interferon-α and interferon-γ response. Post hoc analysis showed pCR rates of 16% (3/19, S1), 77% (10/13, S2) and 80% (12/15, S3) (P = 0.006). In conclusion, neoadjuvant gemcitabine–cisplatin plus tislelizumab for MIBC was compatible with an enhanced pCR rate. Li et al. perform a phase 2 single-arm clinical trial of neoadjuvant chemotherapy plus checkpoint blockade in participants with resectable muscle-invasive bladder cancer and conduct genomic and transcriptomic profiling to describe molecular subtypes.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1465-1478"},"PeriodicalIF":23.5,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142175803","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":"Integrative proteogenomic profiling of high-risk prostate cancer samples from Chinese patients indicates metabolic vulnerabilities and diagnostic biomarkers","authors":"Baijun Dong, Jun-Yu Xu, Yuqi Huang, Jiacheng Guo, Qun Dong, Yanqing Wang, Ni Li, Qiuli Liu, Mingya Zhang, Qiang Pan, Hanling Wang, Jun Jiang, Bairun Chen, Danqing Shen, Yiming Ma, Linhui Zhai, Jian Zhang, Jing Li, Wei Xue, Minjia Tan, Jun Qin","doi":"10.1038/s43018-024-00820-2","DOIUrl":"10.1038/s43018-024-00820-2","url":null,"abstract":"Prostate cancer (PCa) exhibits significant geoethnic disparities as reflected by distinct variations in the cancer genome and disease progression. Here, we perform a comprehensive proteogenomic characterization of localized high-risk PCa utilizing paired tumors and nearby tissues from 125 Chinese male patients, with the primary objectives of identifying potential biomarkers, unraveling critical oncogenic events and delineating molecular subtypes with poor prognosis. Our integrated analysis highlights the utility of GOLM1 as a noninvasive serum biomarker. Phosphoproteomics analysis reveals the crucial role of Ser331 phosphorylation on FOXA1 in regulating FOXA1-AR-dependent cistrome. Notably, our proteomic profiling identifies three distinct subtypes, with metabolic immune-desert tumors (S-III) emerging as a particularly aggressive subtype linked to poor prognosis and BCAT2 catabolism-driven PCa progression. In summary, our study provides a comprehensive resource detailing the unique proteomic and phosphoproteomic characteristics of PCa molecular pathogenesis and offering valuable insights for the development of diagnostic and therapeutic strategies. Dong et al. present an integrative proteogenomic analysis of high-risk prostate cancer samples from a cohort of Chinese patients and highlight potential therapeutic vulnerabilities and diagnostic markers.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 9","pages":"1427-1447"},"PeriodicalIF":23.5,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145987","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":"A protein expression atlas on tissue samples and cell lines from cancer patients provides insights into tumor heterogeneity and dependencies","authors":"Jun Li, Wei Liu, Kamalika Mojumdar, Hong Kim, Zhicheng Zhou, Zhenlin Ju, Shwetha V. Kumar, Patrick Kwok-Shing Ng, Han Chen, Michael A. Davies, Yiling Lu, Rehan Akbani, Gordon B. Mills, Han Liang","doi":"10.1038/s43018-024-00817-x","DOIUrl":"10.1038/s43018-024-00817-x","url":null,"abstract":"The Cancer Genome Atlas (TCGA) and the Cancer Cell Line Encyclopedia (CCLE) are foundational resources in cancer research, providing extensive molecular and phenotypic data. However, large-scale proteomic data across various cancer types for these cohorts remain limited. Here, we expand upon our previous work to generate high-quality protein expression data for approximately 8,000 TCGA patient samples and around 900 CCLE cell line samples, covering 447 clinically relevant proteins, using reverse-phase protein arrays. These protein expression profiles offer profound insights into intertumor heterogeneity and cancer dependency and serve as sensitive functional readouts for somatic alterations. We develop a systematic protein-centered strategy for identifying synthetic lethality pairs and experimentally validate an interaction between protein kinase A subunit α and epidermal growth factor receptor. We also identify metastasis-related protein markers with clinical relevance. This dataset represents a valuable resource for advancing our understanding of cancer mechanisms, discovering protein biomarkers and developing innovative therapeutic strategies. Liang and colleagues establish a high-quality protein expression resource for 8,000 The Cancer Genome Atlas patient samples and 900 Cancer Cell Line Encyclopedia cell lines for approximately 450 proteins, which they use to identify synthetic lethality pairs and metastasis markers.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1579-1595"},"PeriodicalIF":23.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142126188","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 IL-17A to combat immune-related adverse events","authors":"Kailan Sierra-Davidson, Genevieve M. Boland","doi":"10.1038/s43018-024-00804-2","DOIUrl":"10.1038/s43018-024-00804-2","url":null,"abstract":"The clinical utility of immune checkpoint inhibitors is limited by immune-related adverse events (irAEs); understanding the mechanisms of irAE development is thus crucial. A study reports that IL-17A-expressing CD4+ T cells were elevated at irAE onset and provides proof of concept for using IL-17A blockade to improve irAEs in two patients.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 9","pages":"1289-1291"},"PeriodicalIF":23.5,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142109653","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}