Pub Date : 2024-04-12DOI: 10.1038/s43018-024-00760-x
Xiangyu Chen, Jing Zhao, Shuai Yue, Ziyu Li, Xiang Duan, Yao Lin, Yang Yang, Junjian He, Leiqiong Gao, Zhiwei Pan, Xiaofan Yang, Xingxing Su, Min Huang, Xiao Li, Ye Zhao, Xuehui Zhang, Zhirong Li, Li Hu, Jianfang Tang, Yaxing Hao, Qin Tian, Yifei Wang, Lifan Xu, Qizhao Huang, Yingjiao Cao, Yaokai Chen, Bo Zhu, Yan Li, Fan Bai, Guozhong Zhang, Lilin Ye
Tumor-specific T cells are crucial in anti-tumor immunity and act as targets for cancer immunotherapies. However, these cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME), leading to inefficacious immunotherapies in most patients with cancer. By contrast, emerging evidence suggested that tumor-irrelevant bystander T (TBYS) cells are abundant and preserve functional memory properties in the TME. To leverage TBYS cells in the TME to eliminate tumor cells, we engineered oncolytic virus (OV) encoding TBYS epitopes (OV-BYTE) to redirect the antigen specificity of tumor cells to pre-existing TBYS cells, leading to effective tumor inhibition in multiple preclinical models. Mechanistically, OV-BYTE induced epitope spreading of tumor antigens to elicit more diverse tumor-specific T cell responses. Remarkably, the OV-BYTE strategy targeting human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory efficiently inhibited tumor progression in a human tumor cell-derived xenograft model, providing important insights into the improvement of cancer immunotherapies in a large population with a history of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination. Ye and colleagues show that an oncolytic virus that delivers tumor-irrelevant bystander T cell epitopes to tumor cells can exploit the abundant population of bystander T cells in the tumor for anti-tumor immunity and potentiate cancer immunotherapy.
肿瘤特异性 T 细胞是抗肿瘤免疫的关键，也是癌症免疫疗法的靶点。然而，这些细胞在肿瘤微环境（TME）中数量稀少、功能衰竭，导致大多数癌症患者的免疫疗法效果不佳。相比之下，新出现的证据表明，与肿瘤无关的旁观者 T 细胞（TBYS）数量丰富，并在肿瘤微环境中保留了功能记忆特性。为了利用TME中的TBYS细胞消灭肿瘤细胞，我们设计了编码TBYS表位的溶瘤病毒（OV）（OV-BYTE），将肿瘤细胞的抗原特异性重定向到预先存在的TBYS细胞，从而在多个临床前模型中有效抑制肿瘤。从机理上讲，OV-BYTE 可诱导肿瘤抗原表位扩散，从而激发更多样化的肿瘤特异性 T 细胞反应。值得注意的是，以人类严重急性呼吸系统综合征冠状病毒2（SARS-CoV-2）特异性T细胞记忆为靶点的OV-BYTE策略有效抑制了人类肿瘤细胞衍生异种移植模型中的肿瘤进展，为改善大量有SARS-CoV-2感染史或冠状病毒病2019（COVID-19）疫苗接种史的人群的癌症免疫疗法提供了重要启示。
{"title":"An oncolytic virus delivering tumor-irrelevant bystander T cell epitopes induces anti-tumor immunity and potentiates cancer immunotherapy","authors":"Xiangyu Chen, Jing Zhao, Shuai Yue, Ziyu Li, Xiang Duan, Yao Lin, Yang Yang, Junjian He, Leiqiong Gao, Zhiwei Pan, Xiaofan Yang, Xingxing Su, Min Huang, Xiao Li, Ye Zhao, Xuehui Zhang, Zhirong Li, Li Hu, Jianfang Tang, Yaxing Hao, Qin Tian, Yifei Wang, Lifan Xu, Qizhao Huang, Yingjiao Cao, Yaokai Chen, Bo Zhu, Yan Li, Fan Bai, Guozhong Zhang, Lilin Ye","doi":"10.1038/s43018-024-00760-x","DOIUrl":"10.1038/s43018-024-00760-x","url":null,"abstract":"Tumor-specific T cells are crucial in anti-tumor immunity and act as targets for cancer immunotherapies. However, these cells are numerically scarce and functionally exhausted in the tumor microenvironment (TME), leading to inefficacious immunotherapies in most patients with cancer. By contrast, emerging evidence suggested that tumor-irrelevant bystander T (TBYS) cells are abundant and preserve functional memory properties in the TME. To leverage TBYS cells in the TME to eliminate tumor cells, we engineered oncolytic virus (OV) encoding TBYS epitopes (OV-BYTE) to redirect the antigen specificity of tumor cells to pre-existing TBYS cells, leading to effective tumor inhibition in multiple preclinical models. Mechanistically, OV-BYTE induced epitope spreading of tumor antigens to elicit more diverse tumor-specific T cell responses. Remarkably, the OV-BYTE strategy targeting human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cell memory efficiently inhibited tumor progression in a human tumor cell-derived xenograft model, providing important insights into the improvement of cancer immunotherapies in a large population with a history of SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination. Ye and colleagues show that an oncolytic virus that delivers tumor-irrelevant bystander T cell epitopes to tumor cells can exploit the abundant population of bystander T cells in the tumor for anti-tumor immunity and potentiate cancer immunotherapy.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 7","pages":"1063-1081"},"PeriodicalIF":23.5,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00760-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140595291","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 : 2024-04-11DOI: 10.1038/s43018-024-00766-5
Zijie Feng, Xin He, Xuyao Zhang, Yuan Wu, Bowen Xing, Alison Knowles, Qiaonan Shan, Samuel Miller, Taylor Hojnacki, Jian Ma, Bryson W. Katona, Terence P. F. Gade, Don L. Siegel, Jörg Schrader, David C. Metz, Carl H. June, Xianxin Hua
{"title":"Author Correction: Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues","authors":"Zijie Feng, Xin He, Xuyao Zhang, Yuan Wu, Bowen Xing, Alison Knowles, Qiaonan Shan, Samuel Miller, Taylor Hojnacki, Jian Ma, Bryson W. Katona, Terence P. F. Gade, Don L. Siegel, Jörg Schrader, David C. Metz, Carl H. June, Xianxin Hua","doi":"10.1038/s43018-024-00766-5","DOIUrl":"10.1038/s43018-024-00766-5","url":null,"abstract":"","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 4","pages":"691-691"},"PeriodicalIF":22.7,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00766-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140714522","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 : 2024-04-02DOI: 10.1038/s43018-024-00754-9
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
The YAP–TEAD protein–protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP–TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP–TEAD protein–protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway. Chapeau et al. develop a nonallosteric inhibitor of the interaction between YAP and all four TEAD proteins. Treatment with the inhibitor, either as monotherapy or in combination with other treatment modalities, leads to induction of cell death in several in vivo cancer models.
{"title":"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/s43018-024-00754-9","DOIUrl":"10.1038/s43018-024-00754-9","url":null,"abstract":"The YAP–TEAD protein–protein interaction mediates YAP oncogenic functions downstream of the Hippo pathway. To date, available YAP–TEAD pharmacologic agents bind into the lipid pocket of TEAD, targeting the interaction indirectly via allosteric changes. However, the consequences of a direct pharmacological disruption of the interface between YAP and TEADs remain largely unexplored. Here, we present IAG933 and its analogs as potent first-in-class and selective disruptors of the YAP–TEAD protein–protein interaction with suitable properties to enter clinical trials. Pharmacologic abrogation of the interaction with all four TEAD paralogs resulted in YAP eviction from chromatin and reduced Hippo-mediated transcription and induction of cell death. In vivo, deep tumor regression was observed in Hippo-driven mesothelioma xenografts at tolerated doses in animal models as well as in Hippo-altered cancer models outside mesothelioma. Importantly this also extended to larger tumor indications, such as lung, pancreatic and colorectal cancer, in combination with RTK, KRAS-mutant selective and MAPK inhibitors, leading to more efficacious and durable responses. Clinical evaluation of IAG933 is underway. Chapeau et al. develop a nonallosteric inhibitor of the interaction between YAP and all four TEAD proteins. Treatment with the inhibitor, either as monotherapy or in combination with other treatment modalities, leads to induction of cell death in several in vivo cancer models.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 7","pages":"1102-1120"},"PeriodicalIF":23.5,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43018-024-00754-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140595574","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 : 2024-04-02DOI: 10.1038/s43018-024-00750-z
A CRISPR dropout screen for tRNA regulators identified YRDC as the top essential gene in glioblastoma stem cells. Threonine acts as a substrate of YRDC to facilitate the N6-threonylcarbamoyladenosine (t6A) tRNA modification and shift translation toward mitosis-related genes with a codon bias. Our findings support targeting glioblastoma growth by a well-tolerated dietary therapy.
{"title":"Threonine fuels brain tumor growth through a conserved tRNA modification","authors":"","doi":"10.1038/s43018-024-00750-z","DOIUrl":"10.1038/s43018-024-00750-z","url":null,"abstract":"A CRISPR dropout screen for tRNA regulators identified YRDC as the top essential gene in glioblastoma stem cells. Threonine acts as a substrate of YRDC to facilitate the N6-threonylcarbamoyladenosine (t6A) tRNA modification and shift translation toward mitosis-related genes with a codon bias. Our findings support targeting glioblastoma growth by a well-tolerated dietary therapy.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 7","pages":"962-963"},"PeriodicalIF":23.5,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140595275","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 : 2024-03-29DOI: 10.1038/s43018-024-00745-w
Jennifer L. Guida, Geehong Hyun, Daniel W. Belsky, Gregory T. Armstrong, Matthew J. Ehrhardt, Melissa M. Hudson, Paige A. Green, Leslie L. Robison, Brennan P. Streck, Emily S. Tonorezos, Yutaka Yasui, Carmen L. Wilson, Zhaoming Wang, Kirsten K. Ness
Survivors of childhood cancer may experience accelerated biological aging, resulting in premature frailty and death. We used seven measures of biological age in the St. Jude Lifetime (SJLIFE) Cohort to compare biological age acceleration between the SJLIFE Cohort and the third United States National Health and Nutrition Examination Survey controls, explore trajectories of biological age according to cancer treatment and type, and test associations of biological age acceleration with frailty and death (mean follow-up of 26.5 years) among survivors. Survivors of cancer aged 5% faster per year and measured, on average, 0.6–6.44 years biologically older compared to controls and 5–16 years biologically older compared to age-matched individuals at the population level. Survivors treated with hematopoietic cell transplant and vinca alkaloid chemotherapy evidenced the fastest trajectories of biological aging. Biologically, older and faster-aging survivors consistently and robustly had a higher risk of frailty and died earlier than those with slower biological aging, suggesting a potential opportunity to intervene on excess aging. Guida et al. assess seven measures of biological age in SJLIFE Cohort and reveal that survivors of cancer age faster than healthy controls and have increased risk of frailty and death. The aging trajectory is further affected by cancer type and therapy.
{"title":"Associations of seven measures of biological age acceleration with frailty and all-cause mortality among adult survivors of childhood cancer in the St. Jude Lifetime Cohort","authors":"Jennifer L. Guida, Geehong Hyun, Daniel W. Belsky, Gregory T. Armstrong, Matthew J. Ehrhardt, Melissa M. Hudson, Paige A. Green, Leslie L. Robison, Brennan P. Streck, Emily S. Tonorezos, Yutaka Yasui, Carmen L. Wilson, Zhaoming Wang, Kirsten K. Ness","doi":"10.1038/s43018-024-00745-w","DOIUrl":"10.1038/s43018-024-00745-w","url":null,"abstract":"Survivors of childhood cancer may experience accelerated biological aging, resulting in premature frailty and death. We used seven measures of biological age in the St. Jude Lifetime (SJLIFE) Cohort to compare biological age acceleration between the SJLIFE Cohort and the third United States National Health and Nutrition Examination Survey controls, explore trajectories of biological age according to cancer treatment and type, and test associations of biological age acceleration with frailty and death (mean follow-up of 26.5 years) among survivors. Survivors of cancer aged 5% faster per year and measured, on average, 0.6–6.44 years biologically older compared to controls and 5–16 years biologically older compared to age-matched individuals at the population level. Survivors treated with hematopoietic cell transplant and vinca alkaloid chemotherapy evidenced the fastest trajectories of biological aging. Biologically, older and faster-aging survivors consistently and robustly had a higher risk of frailty and died earlier than those with slower biological aging, suggesting a potential opportunity to intervene on excess aging. Guida et al. assess seven measures of biological age in SJLIFE Cohort and reveal that survivors of cancer age faster than healthy controls and have increased risk of frailty and death. The aging trajectory is further affected by cancer type and therapy.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 5","pages":"731-741"},"PeriodicalIF":22.7,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140326882","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 : 2024-03-29DOI: 10.1038/s43018-024-00737-w
Judith E. Carroll, Jeanne S. Mandelblatt
A study reports that survivors of childhood cancer age faster than healthy controls and have increased risk of frailty and death; however, heterogeneity in outcomes was present, indicating inequities in risk. Knowledge about aging in high-risk groups holds the potential to identify interventions to improve survivorship outcomes.
{"title":"Disparities, aging and childhood cancer","authors":"Judith E. Carroll, Jeanne S. Mandelblatt","doi":"10.1038/s43018-024-00737-w","DOIUrl":"10.1038/s43018-024-00737-w","url":null,"abstract":"A study reports that survivors of childhood cancer age faster than healthy controls and have increased risk of frailty and death; however, heterogeneity in outcomes was present, indicating inequities in risk. Knowledge about aging in high-risk groups holds the potential to identify interventions to improve survivorship outcomes.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 5","pages":"695-696"},"PeriodicalIF":22.7,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140322607","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 : 2024-03-27DOI: 10.1038/s43018-024-00735-y
Hans R. Widlund, Lydia Lynch
Identifying which patients will benefit most from immune checkpoint blockade (ICB) is an important clinical challenge. A study now finds that Vδ1+ γδ T cells are associated with better response to ICB in melanoma tumors with a lower neoantigen load and shows that some effector functions of PD-1+ Vδ1+ T cells are repressed after engagement of PD-1 by PD-L1.
{"title":"γδ T cells as unconventional targets of checkpoint blockade","authors":"Hans R. Widlund, Lydia Lynch","doi":"10.1038/s43018-024-00735-y","DOIUrl":"10.1038/s43018-024-00735-y","url":null,"abstract":"Identifying which patients will benefit most from immune checkpoint blockade (ICB) is an important clinical challenge. A study now finds that Vδ1+ γδ T cells are associated with better response to ICB in melanoma tumors with a lower neoantigen load and shows that some effector functions of PD-1+ Vδ1+ T cells are repressed after engagement of PD-1 by PD-L1.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 3","pages":"373-374"},"PeriodicalIF":22.7,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306272","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 : 2024-03-27DOI: 10.1038/s43018-023-00708-7
Laura Leonhardt, Matthias Hebrok
Effectively targeting deregulated KRAS signaling remains an unmet clinical need, as current approaches commonly lead to the development of chemoresistance in clinical settings. ADAM9-mediated lysosomal KRAS degradation is now shown to counteract PDAC chemoresistance independently of mutational status.
{"title":"KRAS degradation averts PDAC chemoresistance","authors":"Laura Leonhardt, Matthias Hebrok","doi":"10.1038/s43018-023-00708-7","DOIUrl":"10.1038/s43018-023-00708-7","url":null,"abstract":"Effectively targeting deregulated KRAS signaling remains an unmet clinical need, as current approaches commonly lead to the development of chemoresistance in clinical settings. ADAM9-mediated lysosomal KRAS degradation is now shown to counteract PDAC chemoresistance independently of mutational status.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 3","pages":"375-377"},"PeriodicalIF":22.7,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140306271","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/s43018-024-00752-x
Maishara Muquith, Magdalena Espinoza, Andrew Elliott, Joanne Xiu, Andreas Seeber, Wafik El-Deiry, Emmanuel S. Antonarakis, Stephanie L. Graff, Michael J. Hall, Hossein Borghaei, Dave S. B. Hoon, Stephen V. Liu, Patrick C. Ma, Rana R. McKay, Trisha Wise-Draper, John Marshall, George W. Sledge, David Spetzler, Hao Zhu, David Hsiehchen
Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers. Hsiehchen and colleagues assess the association between tumor mutational burden and survival in a real-world cohort of patients with microsatellite-stable cancers.
{"title":"Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers","authors":"Maishara Muquith, Magdalena Espinoza, Andrew Elliott, Joanne Xiu, Andreas Seeber, Wafik El-Deiry, Emmanuel S. Antonarakis, Stephanie L. Graff, Michael J. Hall, Hossein Borghaei, Dave S. B. Hoon, Stephen V. Liu, Patrick C. Ma, Rana R. McKay, Trisha Wise-Draper, John Marshall, George W. Sledge, David Spetzler, Hao Zhu, David Hsiehchen","doi":"10.1038/s43018-024-00752-x","DOIUrl":"10.1038/s43018-024-00752-x","url":null,"abstract":"Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers. Hsiehchen and colleagues assess the association between tumor mutational burden and survival in a real-world cohort of patients with microsatellite-stable cancers.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 7","pages":"1121-1129"},"PeriodicalIF":23.5,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140288508","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 : 2024-03-22DOI: 10.1038/s43018-024-00747-8
Johanna A. Joyce
Johanna Joyce received her PhD from the University of Cambridge, and did postdoctoral research at the University of California, San Francisco. She then joined the faculty at Memorial Sloan Kettering Cancer Center, New York, becoming a tenured member in 2014. She moved to Switzerland in 2016, where she later served as the inaugural executive director of the Agora Cancer Center Lausanne. She is currently a member of the Ludwig Institute for Cancer Research and a professor at the University of Lausanne.
Johanna Joyce 在剑桥大学获得博士学位，并在加州大学旧金山分校从事博士后研究。随后，她加入纽约斯隆-凯特琳纪念癌症中心任教，并于2014年成为终身教职员工。她于2016年移居瑞士，随后担任洛桑Agora癌症中心的首任执行主任。目前，她是路德维希癌症研究所成员和洛桑大学教授。
{"title":"Trans-Atlantic twists and turns","authors":"Johanna A. Joyce","doi":"10.1038/s43018-024-00747-8","DOIUrl":"10.1038/s43018-024-00747-8","url":null,"abstract":"Johanna Joyce received her PhD from the University of Cambridge, and did postdoctoral research at the University of California, San Francisco. She then joined the faculty at Memorial Sloan Kettering Cancer Center, New York, becoming a tenured member in 2014. She moved to Switzerland in 2016, where she later served as the inaugural executive director of the Agora Cancer Center Lausanne. She is currently a member of the Ludwig Institute for Cancer Research and a professor at the University of Lausanne.","PeriodicalId":18885,"journal":{"name":"Nature cancer","volume":"5 5","pages":"693-694"},"PeriodicalIF":22.7,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140194215","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：