Pub Date : 2024-06-25DOI: 10.1038/s43018-024-00780-7
Michele De Palma, Douglas Hanahan
Research into the mechanisms and manifestations of solid tumor vascularization was launched more than 50 years ago with the proposition and experimental demonstrations that angiogenesis is instrumental for tumor growth and was, therefore, a promising therapeutic target. The biological knowledge and therapeutic insights forthcoming have been remarkable, punctuated by new concepts, many of which were not foreseen in the early decades. This article presents a perspective on tumor vascularization and its therapeutic targeting but does not portray a historical timeline. Rather, we highlight eight conceptual milestones, integrating initial discoveries and recent progress and posing open questions for the future. De Palma and Hanahan outline advances in understanding tumor angiogenesis and discuss the therapeutic opportunities of targeting tumor vascularization.
{"title":"Milestones in tumor vascularization and its therapeutic targeting","authors":"Michele De Palma, Douglas Hanahan","doi":"10.1038/s43018-024-00780-7","DOIUrl":"10.1038/s43018-024-00780-7","url":null,"abstract":"Research into the mechanisms and manifestations of solid tumor vascularization was launched more than 50 years ago with the proposition and experimental demonstrations that angiogenesis is instrumental for tumor growth and was, therefore, a promising therapeutic target. The biological knowledge and therapeutic insights forthcoming have been remarkable, punctuated by new concepts, many of which were not foreseen in the early decades. This article presents a perspective on tumor vascularization and its therapeutic targeting but does not portray a historical timeline. Rather, we highlight eight conceptual milestones, integrating initial discoveries and recent progress and posing open questions for the future. De Palma and Hanahan outline advances in understanding tumor angiogenesis and discuss the therapeutic opportunities of targeting tumor vascularization.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 6","pages":"827-843"},"PeriodicalIF":23.5,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450855","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 : 2024-06-20DOI: 10.1038/s43018-024-00785-2
Kevin P. Letscher, Sai T. Reddy
At present, six CAR-T therapies are FDA approved to treat hematological cancers, but not all patients respond. A new study has developed a multidimensional functional profiling method to screen CAR-T cells from patients with large B cell lymphomas in clinical trials and identified a T cell subset associated with successful clinical response.
{"title":"Multidimensional analysis reveals predictive markers for CAR-T efficacy","authors":"Kevin P. Letscher, Sai T. Reddy","doi":"10.1038/s43018-024-00785-2","DOIUrl":"10.1038/s43018-024-00785-2","url":null,"abstract":"At present, six CAR-T therapies are FDA approved to treat hematological cancers, but not all patients respond. A new study has developed a multidimensional functional profiling method to screen CAR-T cells from patients with large B cell lymphomas in clinical trials and identified a T cell subset associated with successful clinical response.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 7","pages":"960-961"},"PeriodicalIF":23.5,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432277","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 : 2024-06-17DOI: 10.1038/s43018-024-00797-y
Emilie A. Chapeau, Laurent Sansregret, Giorgio G. Galli, Patrick Chène, Markus Wartmann, Thanos P. Mourikis, Patricia Jaaks, Sabrina Baltschukat, Ines A. M. Barbosa, Daniel Bauer, Saskia M. Brachmann, Clara Delaunay, Claire Estadieu, Jason E. Faris, Pascal Furet, Stefanie Harlfinger, Andreas Hueber, Eloísa Jiménez Núñez, David P. Kodack, Emeline Mandon, Typhaine Martin, Yannick Mesrouze, Vincent Romanet, Clemens Scheufler, Holger Sellner, Christelle Stamm, Dario Sterker, Luca Tordella, Francesco Hofmann, Nicolas Soldermann, Tobias Schmelzle
{"title":"Author Correction: Direct and selective pharmacological disruption of the YAP–TEAD interface by IAG933 inhibits Hippo-dependent and RAS–MAPK-altered cancers","authors":"Emilie A. Chapeau, Laurent Sansregret, Giorgio G. Galli, Patrick Chène, Markus Wartmann, Thanos P. Mourikis, Patricia Jaaks, Sabrina Baltschukat, Ines A. M. Barbosa, Daniel Bauer, Saskia M. Brachmann, Clara Delaunay, Claire Estadieu, Jason E. Faris, Pascal Furet, Stefanie Harlfinger, Andreas Hueber, Eloísa Jiménez Núñez, David P. Kodack, Emeline Mandon, Typhaine Martin, Yannick Mesrouze, Vincent Romanet, Clemens Scheufler, Holger Sellner, Christelle Stamm, Dario Sterker, Luca Tordella, Francesco Hofmann, Nicolas Soldermann, Tobias Schmelzle","doi":"10.1038/s43018-024-00797-y","DOIUrl":"10.1038/s43018-024-00797-y","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 7","pages":"1130-1130"},"PeriodicalIF":23.5,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11286518/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419845","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 : 2024-06-06DOI: 10.1038/s43018-024-00771-8
Tommaso Scolaro, Marta Manco, Mathieu Pecqueux, Ricardo Amorim, Rosa Trotta, Heleen H. Van Acker, Matthias Van Haele, Niranjan Shirgaonkar, Stefan Naulaerts, Jan Daniluk, Fran Prenen, Chiara Varamo, Donatella Ponti, Ginevra Doglioni, Ana Margarida Ferreira Campos, Juan Fernandez Garcia, Silvia Radenkovic, Pegah Rouhi, Aleksandar Beatovic, Liwei Wang, Yu Wang, Amalia Tzoumpa, Asier Antoranz, Ara Sargsian, Mario Di Matteo, Emanuele Berardi, Jermaine Goveia, Bart Ghesquière, Tania Roskams, Stefaan Soenen, Thomas Voets, Bella Manshian, Sarah-Maria Fendt, Peter Carmeliet, Abhishek D. Garg, Ramanuj DasGupta, Baki Topal, Massimiliano Mazzone
Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy. Scolaro et al. identify the enzyme cytidine deaminase (CDA) as upregulated in immunotherapy-resistant tumors and find it contributes to the UDP pool, which in turn modulates tumor-associated macrophages to instruct an immune-evasive TME.
{"title":"Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance","authors":"Tommaso Scolaro, Marta Manco, Mathieu Pecqueux, Ricardo Amorim, Rosa Trotta, Heleen H. Van Acker, Matthias Van Haele, Niranjan Shirgaonkar, Stefan Naulaerts, Jan Daniluk, Fran Prenen, Chiara Varamo, Donatella Ponti, Ginevra Doglioni, Ana Margarida Ferreira Campos, Juan Fernandez Garcia, Silvia Radenkovic, Pegah Rouhi, Aleksandar Beatovic, Liwei Wang, Yu Wang, Amalia Tzoumpa, Asier Antoranz, Ara Sargsian, Mario Di Matteo, Emanuele Berardi, Jermaine Goveia, Bart Ghesquière, Tania Roskams, Stefaan Soenen, Thomas Voets, Bella Manshian, Sarah-Maria Fendt, Peter Carmeliet, Abhishek D. Garg, Ramanuj DasGupta, Baki Topal, Massimiliano Mazzone","doi":"10.1038/s43018-024-00771-8","DOIUrl":"10.1038/s43018-024-00771-8","url":null,"abstract":"Many individuals with cancer are resistant to immunotherapies. Here, we identify the gene encoding the pyrimidine salvage pathway enzyme cytidine deaminase (CDA) among the top upregulated metabolic genes in several immunotherapy-resistant tumors. We show that CDA in cancer cells contributes to the uridine diphosphate (UDP) pool. Extracellular UDP hijacks immunosuppressive tumor-associated macrophages (TAMs) through its receptor P2Y6. Pharmacologic or genetic inhibition of CDA in cancer cells (or P2Y6 in TAMs) disrupts TAM-mediated immunosuppression, promoting cytotoxic T cell entry and susceptibility to anti-programmed cell death protein 1 (anti-PD-1) treatment in resistant pancreatic ductal adenocarcinoma (PDAC) and melanoma models. Conversely, CDA overexpression in CDA-depleted PDACs or anti-PD-1-responsive colorectal tumors or systemic UDP administration (re)establishes resistance. In individuals with PDAC, high CDA levels in cancer cells correlate with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1 resistance. In a pan-cancer single-cell atlas, CDAhigh cancer cells match with T cell cytotoxicity dysfunction and P2RY6high TAMs. Overall, we suggest CDA and P2Y6 as potential targets for cancer immunotherapy. Scolaro et al. identify the enzyme cytidine deaminase (CDA) as upregulated in immunotherapy-resistant tumors and find it contributes to the UDP pool, which in turn modulates tumor-associated macrophages to instruct an immune-evasive TME.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 8","pages":"1206-1226"},"PeriodicalIF":23.5,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00771-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141284214","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 : 2024-06-03DOI: 10.1038/s43018-024-00775-4
Kevin M. Tharp, Kelly Kersten, Ori Maller, Greg A. Timblin, Connor Stashko, Fernando P. Canale, Rosa E. Menjivar, Mary-Kate Hayward, Ilona Berestjuk, Johanna ten Hoeve, Bushra Samad, Alastrair J. Ironside, Marina Pasca di Magliano, Alexander Muir, Roger Geiger, Alexis J. Combes, Valerie M. Weaver
Tumor progression is accompanied by fibrosis, a condition of excessive extracellular matrix accumulation, which is associated with diminished antitumor immune infiltration. Here we demonstrate that tumor-associated macrophages (TAMs) respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a collagen biosynthesis program directed by transforming growth factor-β. A collateral effect of this programming is an untenable metabolic milieu for productive CD8+ T cell antitumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline and secrete ornithine that compromises CD8+ T cell function in female breast cancer. Thus, a stiff and fibrotic TME may impede antitumor immunity not only by direct physical exclusion of CD8+ T cells but also through secondary effects of a mechano-metabolic programming of TAMs, which creates an inhospitable metabolic milieu for CD8+ T cells to respond to anticancer immunotherapies. Weaver and colleagues show that TGFβ-induced collagen deposition and metabolic reprogramming of the breast cancer microenvironment by tumor-associated macrophages restrict the antitumor activity of CD8+ T cells in female breast cancer.
肿瘤进展伴随着纤维化，这是一种细胞外基质过度积累的情况，与抗肿瘤免疫浸润减少有关。在这里，我们证明了肿瘤相关巨噬细胞（TAMs）通过启动由转化生长因子-β引导的胶原蛋白生物合成程序来应对僵化的纤维化肿瘤微环境（TME）。由于胶原合成巨噬细胞会消耗环境中的精氨酸、合成脯氨酸并分泌鸟氨酸，从而损害了 CD8+ T 细胞在女性乳腺癌中的功能。因此，僵硬和纤维化的 TME 可能不仅通过直接物理排斥 CD8+ T 细胞，而且还通过 TAMs 机械代谢程序的继发效应阻碍抗肿瘤免疫，这为 CD8+ T 细胞对抗癌免疫疗法做出反应创造了一个不适宜的代谢环境。
{"title":"Tumor-associated macrophages restrict CD8+ T cell function through collagen deposition and metabolic reprogramming of the breast cancer microenvironment","authors":"Kevin M. Tharp, Kelly Kersten, Ori Maller, Greg A. Timblin, Connor Stashko, Fernando P. Canale, Rosa E. Menjivar, Mary-Kate Hayward, Ilona Berestjuk, Johanna ten Hoeve, Bushra Samad, Alastrair J. Ironside, Marina Pasca di Magliano, Alexander Muir, Roger Geiger, Alexis J. Combes, Valerie M. Weaver","doi":"10.1038/s43018-024-00775-4","DOIUrl":"10.1038/s43018-024-00775-4","url":null,"abstract":"Tumor progression is accompanied by fibrosis, a condition of excessive extracellular matrix accumulation, which is associated with diminished antitumor immune infiltration. Here we demonstrate that tumor-associated macrophages (TAMs) respond to the stiffened fibrotic tumor microenvironment (TME) by initiating a collagen biosynthesis program directed by transforming growth factor-β. A collateral effect of this programming is an untenable metabolic milieu for productive CD8+ T cell antitumor responses, as collagen-synthesizing macrophages consume environmental arginine, synthesize proline and secrete ornithine that compromises CD8+ T cell function in female breast cancer. Thus, a stiff and fibrotic TME may impede antitumor immunity not only by direct physical exclusion of CD8+ T cells but also through secondary effects of a mechano-metabolic programming of TAMs, which creates an inhospitable metabolic milieu for CD8+ T cells to respond to anticancer immunotherapies. Weaver and colleagues show that TGFβ-induced collagen deposition and metabolic reprogramming of the breast cancer microenvironment by tumor-associated macrophages restrict the antitumor activity of CD8+ T cells in female breast cancer.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 7","pages":"1045-1062"},"PeriodicalIF":23.5,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141238107","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 : 2024-06-03DOI: 10.1038/s43018-024-00758-5
Matthew D. Perricone, Costas A. Lyssiotis
Tumor fibrosis is known to suppress anti-tumor immunity. A new study now highlights the role of tumor-associated macrophages in coordinating fibrosis-mediated metabolic changes in tumors, restricting cytotoxic T cell responses and contributing to tumor growth.
{"title":"Fibrotic tumors tune metabolism for immune evasion","authors":"Matthew D. Perricone, Costas A. Lyssiotis","doi":"10.1038/s43018-024-00758-5","DOIUrl":"10.1038/s43018-024-00758-5","url":null,"abstract":"Tumor fibrosis is known to suppress anti-tumor immunity. A new study now highlights the role of tumor-associated macrophages in coordinating fibrosis-mediated metabolic changes in tumors, restricting cytotoxic T cell responses and contributing to tumor growth.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 7","pages":"955-957"},"PeriodicalIF":23.5,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141238100","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 : 2024-06-03DOI: 10.1038/s43018-024-00772-7
Tian-Gen Chang, Yingying Cao, Hannah J. Sfreddo, Saugato Rahman Dhruba, Se-Hoon Lee, Cristina Valero, Seong-Keun Yoo, Diego Chowell, Luc G. T. Morris, Eytan Ruppin
Despite the revolutionary impact of immune checkpoint blockade (ICB) in cancer treatment, accurately predicting patient responses remains challenging. Here, we analyzed a large dataset of 2,881 ICB-treated and 841 non-ICB-treated patients across 18 solid tumor types, encompassing a wide range of clinical, pathologic and genomic features. We developed a clinical score called LORIS (logistic regression-based immunotherapy-response score) using a six-feature logistic regression model. LORIS outperforms previous signatures in predicting ICB response and identifying responsive patients even with low tumor mutational burden or programmed cell death 1 ligand 1 expression. LORIS consistently predicts patient objective response and short-term and long-term survival across most cancer types. Moreover, LORIS showcases a near-monotonic relationship with ICB response probability and patient survival, enabling precise patient stratification. As an accurate, interpretable method using a few readily measurable features, LORIS may help improve clinical decision-making in precision medicine to maximize patient benefit. LORIS is available as an online tool at https://loris.ccr.cancer.gov/ . Chang et al. performed a pan-cancer multimodal data integration analysis and devised a model, LORIS, that can predict objective responses to immunotherapy and patient survival across many cancer types and allow for patient stratification.
{"title":"LORIS robustly predicts patient outcomes with immune checkpoint blockade therapy using common clinical, pathologic and genomic features","authors":"Tian-Gen Chang, Yingying Cao, Hannah J. Sfreddo, Saugato Rahman Dhruba, Se-Hoon Lee, Cristina Valero, Seong-Keun Yoo, Diego Chowell, Luc G. T. Morris, Eytan Ruppin","doi":"10.1038/s43018-024-00772-7","DOIUrl":"10.1038/s43018-024-00772-7","url":null,"abstract":"Despite the revolutionary impact of immune checkpoint blockade (ICB) in cancer treatment, accurately predicting patient responses remains challenging. Here, we analyzed a large dataset of 2,881 ICB-treated and 841 non-ICB-treated patients across 18 solid tumor types, encompassing a wide range of clinical, pathologic and genomic features. We developed a clinical score called LORIS (logistic regression-based immunotherapy-response score) using a six-feature logistic regression model. LORIS outperforms previous signatures in predicting ICB response and identifying responsive patients even with low tumor mutational burden or programmed cell death 1 ligand 1 expression. LORIS consistently predicts patient objective response and short-term and long-term survival across most cancer types. Moreover, LORIS showcases a near-monotonic relationship with ICB response probability and patient survival, enabling precise patient stratification. As an accurate, interpretable method using a few readily measurable features, LORIS may help improve clinical decision-making in precision medicine to maximize patient benefit. LORIS is available as an online tool at https://loris.ccr.cancer.gov/ . Chang et al. performed a pan-cancer multimodal data integration analysis and devised a model, LORIS, that can predict objective responses to immunotherapy and patient survival across many cancer types and allow for patient stratification.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 8","pages":"1158-1175"},"PeriodicalIF":23.5,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141238104","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 : 2024-05-30DOI: 10.1038/s43018-024-00778-1
Charles E. de Bock, Jan Cools
Targeted therapies that use small-molecule inhibitors for the treatment of T cell blood cancer exist only for certain subtypes, and the development of immunologically based CAR T cell therapies has been challenging. A study now exploits the fact that malignant T cells express one of two T cell receptor-β variants and investigates strategies for targeting these malignant cells while sparing half of the non-malignant T cells.
{"title":"Selective targeting of malignant T cells","authors":"Charles E. de Bock, Jan Cools","doi":"10.1038/s43018-024-00778-1","DOIUrl":"10.1038/s43018-024-00778-1","url":null,"abstract":"Targeted therapies that use small-molecule inhibitors for the treatment of T cell blood cancer exist only for certain subtypes, and the development of immunologically based CAR T cell therapies has been challenging. A study now exploits the fact that malignant T cells express one of two T cell receptor-β variants and investigates strategies for targeting these malignant cells while sparing half of the non-malignant T cells.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 6","pages":"823-824"},"PeriodicalIF":23.5,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180389","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 : 2024-05-30DOI: 10.1038/s43018-024-00746-9
Julia Höbart, Jürgen Ruland
T cell receptor (TCR)-engineered T cells offer great promise for targeting tumor antigens in cancer therapy. A synthetic fusion protein termed 80BB, which can simultaneously activate the CD28 and 4-1BB co-stimulatory pathways, is now shown to enhance overall functionality of therapeutic TCR/CD3-dependent T cells in an antigen-agnostic manner.
{"title":"Constructing co-stimulation to boost TCR therapy","authors":"Julia Höbart, Jürgen Ruland","doi":"10.1038/s43018-024-00746-9","DOIUrl":"10.1038/s43018-024-00746-9","url":null,"abstract":"T cell receptor (TCR)-engineered T cells offer great promise for targeting tumor antigens in cancer therapy. A synthetic fusion protein termed 80BB, which can simultaneously activate the CD28 and 4-1BB co-stimulatory pathways, is now shown to enhance overall functionality of therapeutic TCR/CD3-dependent T cells in an antigen-agnostic manner.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 5","pages":"697-698"},"PeriodicalIF":22.7,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178546","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 : 2024-05-30DOI: 10.1038/s43018-024-00782-5
Lois M. Kelly, Justine C. Rutter, Kevin H. Lin, Frank Ling, Matthieu Duchmann, Emmanuelle Latour, Nadia Arang, Hélène Pasquer, Duong Ho Nhat, Juliette Charles, Shane T. Killarney, Hazel X. Ang, Federica Namor, Cécile Culeux, Bérangère Lombard, Damarys Loew, Danielle L. Swaney, Nevan J. Krogan, Luc Brunel, Élodie Carretero, Pascal Verdié, Muriel Amblard, Sofiane Fodil, Tony Huynh, Marie Sebert, Lionel Adès, Emmanuel Raffoux, Nina Fenouille, Raphaël Itzykson, Camille Lobry, Lina Benajiba, Antoine Forget, Anthony R. Martin, Kris C. Wood, Alexandre Puissant
Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ–PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models. Puissant and colleagues identify a myeloid-restricted PIK3CG/p110γ–PIK3R5/p101 axis as a therapeutic vulnerability in acute myeloid leukemia and develop a proteolysis-targeting chimera to potently degrade PIK3CG and suppress AML progression.
剂量限制性毒性是癌症靶向疗法临床应用的一个主要限制因素，通常是由非恶性组织中的靶点参与引起的。通过靶向受组织限制和/或肿瘤限制表达的蛋白质所驱动的癌症依赖性，可以最大限度地减少这一障碍。与最近的另一篇报道一致，我们在此表明，在急性髓性白血病（AML）中，抑制髓限制性 PIK3CG/p110γ-PIK3R5/p101 轴可抑制蛋白激酶 B/Akt 信号转导，并损害 AML 细胞的健康。此外，沉默编码 PIK3CG/p110γ 或 PIK3R5/p101 的基因会使 AML 细胞对现有的 AML 疗法敏感。重要的是，我们发现现有的 PIK3CG 小分子抑制剂不足以实现长期持续的抗白血病效果。为了解决这个问题，我们开发了一种蛋白水解靶向嵌合体（PROTAC）异功能分子，它能特异性降解 PIK3CG，在人类急性髓细胞白血病细胞系、急性髓细胞白血病患者的原始样本和合成小鼠模型中单独或与 Venetoclax 联用都能有效抑制急性髓细胞白血病的进展。
{"title":"Targeting a lineage-specific PI3Kɣ–Akt signaling module in acute myeloid leukemia using a heterobifunctional degrader molecule","authors":"Lois M. Kelly, Justine C. Rutter, Kevin H. Lin, Frank Ling, Matthieu Duchmann, Emmanuelle Latour, Nadia Arang, Hélène Pasquer, Duong Ho Nhat, Juliette Charles, Shane T. Killarney, Hazel X. Ang, Federica Namor, Cécile Culeux, Bérangère Lombard, Damarys Loew, Danielle L. Swaney, Nevan J. Krogan, Luc Brunel, Élodie Carretero, Pascal Verdié, Muriel Amblard, Sofiane Fodil, Tony Huynh, Marie Sebert, Lionel Adès, Emmanuel Raffoux, Nina Fenouille, Raphaël Itzykson, Camille Lobry, Lina Benajiba, Antoine Forget, Anthony R. Martin, Kris C. Wood, Alexandre Puissant","doi":"10.1038/s43018-024-00782-5","DOIUrl":"10.1038/s43018-024-00782-5","url":null,"abstract":"Dose-limiting toxicity poses a major limitation to the clinical utility of targeted cancer therapies, often arising from target engagement in nonmalignant tissues. This obstacle can be minimized by targeting cancer dependencies driven by proteins with tissue-restricted and/or tumor-restricted expression. In line with another recent report, we show here that, in acute myeloid leukemia (AML), suppression of the myeloid-restricted PIK3CG/p110γ–PIK3R5/p101 axis inhibits protein kinase B/Akt signaling and compromises AML cell fitness. Furthermore, silencing the genes encoding PIK3CG/p110γ or PIK3R5/p101 sensitizes AML cells to established AML therapies. Importantly, we find that existing small-molecule inhibitors against PIK3CG are insufficient to achieve a sustained long-term antileukemic effect. To address this concern, we developed a proteolysis-targeting chimera (PROTAC) heterobifunctional molecule that specifically degrades PIK3CG and potently suppresses AML progression alone and in combination with venetoclax in human AML cell lines, primary samples from patients with AML and syngeneic mouse models. Puissant and colleagues identify a myeloid-restricted PIK3CG/p110γ–PIK3R5/p101 axis as a therapeutic vulnerability in acute myeloid leukemia and develop a proteolysis-targeting chimera to potently degrade PIK3CG and suppress AML progression.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 7","pages":"1082-1101"},"PeriodicalIF":23.5,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141178109","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}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：