Nature cancer最新文献

{"title":"Spatial analysis reveals targetable macrophage-mediated mechanisms of immune evasion in hepatocellular carcinoma minimal residual disease","authors":"Lea Lemaitre, Nia Adeniji, Akanksha Suresh, Reshma Reguram, Josephine Zhang, Jangho Park, Amit Reddy, Alexandro E. Trevino, Aaron T. Mayer, Anja Deutzmann, Aida S. Hansen, Ling Tong, Vinodhini Arjunan, Neeraja Kambham, Brendan C. Visser, Monica M. Dua, C. Andrew Bonham, Nishita Kothary, H. Blaize D’Angio, Ryan Preska, Yanay Rosen, James Zou, Vivek Charu, Dean W. Felsher, Renumathy Dhanasekaran","doi":"10.1038/s43018-024-00828-8","DOIUrl":"10.1038/s43018-024-00828-8","url":null,"abstract":"Hepatocellular carcinoma (HCC) frequently recurs from minimal residual disease (MRD), which persists after therapy. Here, we identified mechanisms of persistence of residual tumor cells using post-chemoembolization human HCC (n = 108 patients, 1.07 million cells) and a transgenic mouse model of MRD. Through single-cell high-plex cytometric imaging, we identified a spatial neighborhood within which PD-L1 + M2-like macrophages interact with stem-like tumor cells, correlating with CD8+ T cell exhaustion and poor survival. Further, through spatial transcriptomics of residual HCC, we showed that macrophage-derived TGFβ1 mediates the persistence of stem-like tumor cells. Last, we demonstrate that combined blockade of Pdl1 and Tgfβ excluded immunosuppressive macrophages, recruited activated CD8+ T cells and eliminated residual stem-like tumor cells in two mouse models: a transgenic model of MRD and a syngeneic orthotopic model of doxorubicin-resistant HCC. Thus, our spatial analyses reveal that PD-L1+ macrophages sustain MRD by activating the TGFβ pathway in stem-like cancer cells and targeting this interaction may prevent HCC recurrence from MRD. Dhanasekaran and colleagues study minimal residual disease in hepatocellular carcinoma using single-cell spatial transcriptomic and proteomic analysis and find a targetable role for immunosuppressive macrophages.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1534-1556"},"PeriodicalIF":23.5,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291578","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":"Leveraging the potential for deintensification in cancer care","authors":"Jennifer A. Soon, Fanny Franchini, Maarten J. IJzerman, Grant A. McArthur","doi":"10.1038/s43018-024-00827-9","DOIUrl":"10.1038/s43018-024-00827-9","url":null,"abstract":"Evidence-based reductions in cancer treatment that still preserve outcomes can result in an improved quality of life for patients and optimized healthcare resourcing. Using melanoma as an example, we define treatment deintensification, outlining barriers to its implementation, as well as existing guidance.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 11","pages":"1597-1599"},"PeriodicalIF":23.5,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142291572","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":"Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses","authors":"Courtney D. DiNardo, Divij Verma, Natalia Baran, Tushar D. Bhagat, Anna Skwarska, Alessia Lodi, Kapil Saxena, Tianyu Cai, Xiaoping Su, Veronica A. Guerra, Gowri Poigaialwar, Vinitha M. Kuruvilla, Sergej Konoplev, Shanisha Gordon-Mitchell, Kith Pradhan, Srinivas Aluri, G. Lavender Hackman, Sovira Chaudhry, Meghan Collins, Shannon R. Sweeney, Jonathan Busquets, Atul Singh Rathore, Qing Deng, Michael R. Green, Steven Grant, Susan Demo, Gaurav S. Choudhary, Srabani Sahu, Beamon Agarwal, Mason Spodek, Victor Thiruthuvanathan, Britta Will, Ulrich Steidl, George D. Tippett, Jan Burger, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Tapan Kadia, Steven Kornblau, Naval G. Daver, Kiran Naqvi, Nicholas J. Short, Guillermo Garcia-Manero, Stefano Tiziani, Amit Verma, Marina Konopleva","doi":"10.1038/s43018-024-00811-3","DOIUrl":"10.1038/s43018-024-00811-3","url":null,"abstract":"Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993 . DiNardo et al. perform a phase 1b/2 clinical trial of telaglenastat (CB-839) in combination with azacytidine in persons with advanced myelodysplastic syndromes and report on the treatment safety and efficacy, including a definition of clinical responders.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 10","pages":"1515-1533"},"PeriodicalIF":23.5,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142253739","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":"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}