Pub Date : 2025-01-08DOI: 10.1158/2159-8290.CD-24-0499
Ángel Fernández-Sanromán, Annika Fendler, Benjy J Y Tan, Anne-Laure Cattin, Charlotte Spencer, Rachael Thompson, Lewis Au, Irene Lobon, Husayn Ahmed Pallikonda, Alice Martin, Fiona Byrne, Antonia Franz, Anna Mikolajczak, Haseeb Rahman, Zayd Tippu, Scott T C Shepherd, Hugang Feng, Daqi Deng, Andrew Rowan, Lisa Pickering, Andrew J S Furness, Kate Young, David Nicol, Sarah Maria Rudman, Tim O'Brien, Kim Edmonds, Ashish Chandra, Steve Hazell, Kevin Litchfield, George Kassiotis, James Larkin, Samra Turajlic
While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy. We also uncover a co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically-relevant and hitherto underappreciated non-genetic evolution patterns in ccRCC.
{"title":"Tracking non-genetic evolution from primary to metastatic ccRCC: TRACERx Renal.","authors":"Ángel Fernández-Sanromán, Annika Fendler, Benjy J Y Tan, Anne-Laure Cattin, Charlotte Spencer, Rachael Thompson, Lewis Au, Irene Lobon, Husayn Ahmed Pallikonda, Alice Martin, Fiona Byrne, Antonia Franz, Anna Mikolajczak, Haseeb Rahman, Zayd Tippu, Scott T C Shepherd, Hugang Feng, Daqi Deng, Andrew Rowan, Lisa Pickering, Andrew J S Furness, Kate Young, David Nicol, Sarah Maria Rudman, Tim O'Brien, Kim Edmonds, Ashish Chandra, Steve Hazell, Kevin Litchfield, George Kassiotis, James Larkin, Samra Turajlic","doi":"10.1158/2159-8290.CD-24-0499","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0499","url":null,"abstract":"<p><p>While the key aspects of genetic evolution and their clinical implications in clear cell renal-cell carcinoma (ccRCC) are well-documented, how genetic features co-evolve with the phenotype and tumor microenvironment (TME) remains elusive. Here, through joint genomic-transcriptomic analysis of 243 samples from 79 patients recruited to the TRACERx Renal study, we identify pervasive non-genetic intratumor heterogeneity, with over 40% not attributable to genetic alterations. By integrating tumor transcriptomes and phylogenetic structures, we observe convergent evolution to specific phenotypic traits, including cell proliferation, metabolic reprogramming and overexpression of putative cGAS-STING repressors amid high aneuploidy. We also uncover a co-evolution between the tumor and the T cell repertoire, as well as a longitudinal shift in the TME from an anti-tumor to an immunosuppressive state, linked to the acquisition of recurrently late ccRCC drivers 9p loss and SETD2 mutations. Our study reveals clinically-relevant and hitherto underappreciated non-genetic evolution patterns in ccRCC.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945085","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 : 2025-01-08DOI: 10.1158/2159-8290.cd-24-0605
Haoran Ma, Supriya Srivastava, Shamaine Wei Ting Ho, Chang Xu, Benedict Shi Xiang Lian, Xuewen Ong, Su Ting Tay, Taotao Sheng, Huey Yew Jeffrey Lum, Siti Aishah Binte Abdul Ghani, Yunqiang Chu, Kie Kyon Huang, Yeek Teck Goh, Minghui Lee, Takeshi Hagihara, Clara Shi Ya Ng, Angie Lay Keng Tan, Yanrong Zhang, Zichen Ding, Feng Zhu, Michelle Shu Wen Ng, Craig Ryan Cecil Joseph, Hui Chen, Zhen Li, Joseph J. Zhao, Sun Young Rha, Ming Teh, Joe Yeong, Wei Peng Yong, Jimmy Bok-Yan So, Raghav Sundar, Patrick Tan
Gastric cancer (GC) is a major cause of global cancer mortality with high levels of heterogeneity. To explore geospatial interactions in tumor ecosystems, we integrated 2,138 spatial transcriptomic regions-of-interest (ROIs) with 152,423 single-cell expression profiles across 226 GC samples from 121 patients. We observed pervasive expression-based intratumor heterogeneity, recapitulating tumor progression through spatially localized and functionally ordered subgroups associated with specific immune microenvironments, checkpoint profiles, and genetic drivers such as SOX9. Evolutionary phylogenetic analysis revealed two different evolutionary trajectories (branched evolution and internal diaspora evolution) associated with distinct molecular subtypes, clinical prognoses, and stromal neighborhoods including VWF+ ACKR1+ endothelial cells. Spatial analysis of tumor-stromal interfaces across multiple GCs highlighted new ecosystem states not attributable to mere tumor/stroma admixture, landmarked by increased GREM1 expression. Our results provide insights into how the cellular ecosystems of individual GCs are sculpted by tumor intrinsic and extrinsic selective pressures, culminating in individualized patient-specific cancer cartographies.
{"title":"Spatially Resolved Tumor Ecosystems and Cell States in Gastric Adenocarcinoma Progression and Evolution","authors":"Haoran Ma, Supriya Srivastava, Shamaine Wei Ting Ho, Chang Xu, Benedict Shi Xiang Lian, Xuewen Ong, Su Ting Tay, Taotao Sheng, Huey Yew Jeffrey Lum, Siti Aishah Binte Abdul Ghani, Yunqiang Chu, Kie Kyon Huang, Yeek Teck Goh, Minghui Lee, Takeshi Hagihara, Clara Shi Ya Ng, Angie Lay Keng Tan, Yanrong Zhang, Zichen Ding, Feng Zhu, Michelle Shu Wen Ng, Craig Ryan Cecil Joseph, Hui Chen, Zhen Li, Joseph J. Zhao, Sun Young Rha, Ming Teh, Joe Yeong, Wei Peng Yong, Jimmy Bok-Yan So, Raghav Sundar, Patrick Tan","doi":"10.1158/2159-8290.cd-24-0605","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0605","url":null,"abstract":"Gastric cancer (GC) is a major cause of global cancer mortality with high levels of heterogeneity. To explore geospatial interactions in tumor ecosystems, we integrated 2,138 spatial transcriptomic regions-of-interest (ROIs) with 152,423 single-cell expression profiles across 226 GC samples from 121 patients. We observed pervasive expression-based intratumor heterogeneity, recapitulating tumor progression through spatially localized and functionally ordered subgroups associated with specific immune microenvironments, checkpoint profiles, and genetic drivers such as SOX9. Evolutionary phylogenetic analysis revealed two different evolutionary trajectories (branched evolution and internal diaspora evolution) associated with distinct molecular subtypes, clinical prognoses, and stromal neighborhoods including VWF+ ACKR1+ endothelial cells. Spatial analysis of tumor-stromal interfaces across multiple GCs highlighted new ecosystem states not attributable to mere tumor/stroma admixture, landmarked by increased GREM1 expression. Our results provide insights into how the cellular ecosystems of individual GCs are sculpted by tumor intrinsic and extrinsic selective pressures, culminating in individualized patient-specific cancer cartographies.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936174","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 : 2025-01-07DOI: 10.1158/2159-8290.cd-24-1071
Yi-Jiun Su, Anne Marijn Kramer, Mark P. Hamilton, Neha Agarwal, Hrishikesh K. Srinagesh, John H. Baird, Bita Sahaf, Adam Kuo, Zachary J. Ehlinger, Moksha H. Desai, Skyler P. Rietberg, Ramya Tunuguntla, Shabnum Patel, Harshini Chinnasamy, Nikolaos Gkitsas-Long, Dorota D. Klysz, Annie Kathleen. Brown, Sushma Bharadwaj, Saurabh Dahiya, Melody Smith, Lori Muffly, Crystal L. Mackall, Zinaida Good, Steven A. Feldman, David B. Miklos, Matthew J. Frank
Patients with large B-cell lymphoma (LBCL) progressing after anti-CD19 CAR T-cell (CAR19) therapy have poor outcomes. Subsequent CAR T-cell therapy shows promise, but the impact of residual CAR19 and early relapse remains unclear. We evaluated 37 CAR19-refractory LBCL patients who received anti-CD22 CAR T-cell (CAR22) in a phase 1b trial (NCT04088890). Residual CAR19 was unquantifiable in 17 of 33 evaluable patients post-CAR22 infusion. Single-cell RNA sequencing revealed minimal CAR19/CAR22 co-transduction. Peak CAR19 transgene levels did not affect CAR22 efficacy or toxicities. CAR22 products from patients undergoing leukapheresis > 6 months post-CAR19 had higher CD4+ naïve T and CD4+/CD8+ T- central memory (TCM) cells, with lower CD4+ T-effector memory cells. High and low percentages of CAR22 TCM and TEM, respectively, were correlated with CAR22 transduction efficiency and achieving complete response. Residual CAR19 and leukapheresis timing did not significantly affect outcomes, while CAR22 product composition was significantly correlated with treatment response.
{"title":"Effects of an initial anti-CD19 CAR T-cell therapy on subsequent anti-CD22 CAR T-cell manufacturing and clinical outcomes in patients with r/r LBCL","authors":"Yi-Jiun Su, Anne Marijn Kramer, Mark P. Hamilton, Neha Agarwal, Hrishikesh K. Srinagesh, John H. Baird, Bita Sahaf, Adam Kuo, Zachary J. Ehlinger, Moksha H. Desai, Skyler P. Rietberg, Ramya Tunuguntla, Shabnum Patel, Harshini Chinnasamy, Nikolaos Gkitsas-Long, Dorota D. Klysz, Annie Kathleen. Brown, Sushma Bharadwaj, Saurabh Dahiya, Melody Smith, Lori Muffly, Crystal L. Mackall, Zinaida Good, Steven A. Feldman, David B. Miklos, Matthew J. Frank","doi":"10.1158/2159-8290.cd-24-1071","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1071","url":null,"abstract":"Patients with large B-cell lymphoma (LBCL) progressing after anti-CD19 CAR T-cell (CAR19) therapy have poor outcomes. Subsequent CAR T-cell therapy shows promise, but the impact of residual CAR19 and early relapse remains unclear. We evaluated 37 CAR19-refractory LBCL patients who received anti-CD22 CAR T-cell (CAR22) in a phase 1b trial (NCT04088890). Residual CAR19 was unquantifiable in 17 of 33 evaluable patients post-CAR22 infusion. Single-cell RNA sequencing revealed minimal CAR19/CAR22 co-transduction. Peak CAR19 transgene levels did not affect CAR22 efficacy or toxicities. CAR22 products from patients undergoing leukapheresis &gt; 6 months post-CAR19 had higher CD4+ naïve T and CD4+/CD8+ T- central memory (TCM) cells, with lower CD4+ T-effector memory cells. High and low percentages of CAR22 TCM and TEM, respectively, were correlated with CAR22 transduction efficiency and achieving complete response. Residual CAR19 and leukapheresis timing did not significantly affect outcomes, while CAR22 product composition was significantly correlated with treatment response.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"28 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936178","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 : 2025-01-07DOI: 10.1158/2159-8290.cd-24-0094
Charles A. Ishak, Sajid A. Marhon, Nairi Tchrakian, Anjelica Hodgson, Helen Loo Yau, Isabela M. Gonzaga, Melanie Peralta, Ilinca M. Lungu, Stephanie Gomez, Sheng-Ben Liang, Shu Yi Shen, Raymond Chen, Jocelyn Chen, Biji Chatterjee, Kevin N. Wanniarachchi, Junwoo Lee, Nicholas Zehrbach, Amir Hosseini, Parinaz Mehdipour, Siyu Sun, Alexander Solovyov, Ilias Ettayebi, Kyle E. Francis, Aobo He, Taiyi Wu, Shengrui Feng, Tiago da Silva Medina, Felipe Campos de Almeida, Jane Bayani, Jason Li, Spencer MacDonald, Yadong Wang, Sarah S. Garcia, Elisa Arthofer, Noor Diab, Aneil Srivastava, Paul Tran. Austin, Peter J.B. Sabatini, Benjamin D. Greenbaum, Catherine A. O'Brien, Trevor G. Shepherd, Ming Sound Tsao, Katherine B. Chiappinelli, Amit M. Oza, Blaise A. Clarke, Robert Rottapel, Stephanie Lheureux, Daniel D. De Carvalho
Epigenetic therapies facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize premalignant lesions of the fallopian tube along with syngeneic epithelial ovarian cancer models to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss permits transcription of immunogenic repetitive elements and chronic viral mimicry activation that increases cellular tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity. This selection process can be partially attenuated pharmacologically. Altogether, these results reveal that viral mimicry conditioning following p53 loss promotes immune evasion and may represent a pharmacological target for early cancer interception.
{"title":"Chronic viral mimicry induction following p53 loss promotes immune evasion","authors":"Charles A. Ishak, Sajid A. Marhon, Nairi Tchrakian, Anjelica Hodgson, Helen Loo Yau, Isabela M. Gonzaga, Melanie Peralta, Ilinca M. Lungu, Stephanie Gomez, Sheng-Ben Liang, Shu Yi Shen, Raymond Chen, Jocelyn Chen, Biji Chatterjee, Kevin N. Wanniarachchi, Junwoo Lee, Nicholas Zehrbach, Amir Hosseini, Parinaz Mehdipour, Siyu Sun, Alexander Solovyov, Ilias Ettayebi, Kyle E. Francis, Aobo He, Taiyi Wu, Shengrui Feng, Tiago da Silva Medina, Felipe Campos de Almeida, Jane Bayani, Jason Li, Spencer MacDonald, Yadong Wang, Sarah S. Garcia, Elisa Arthofer, Noor Diab, Aneil Srivastava, Paul Tran. Austin, Peter J.B. Sabatini, Benjamin D. Greenbaum, Catherine A. O'Brien, Trevor G. Shepherd, Ming Sound Tsao, Katherine B. Chiappinelli, Amit M. Oza, Blaise A. Clarke, Robert Rottapel, Stephanie Lheureux, Daniel D. De Carvalho","doi":"10.1158/2159-8290.cd-24-0094","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0094","url":null,"abstract":"Epigenetic therapies facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize premalignant lesions of the fallopian tube along with syngeneic epithelial ovarian cancer models to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss permits transcription of immunogenic repetitive elements and chronic viral mimicry activation that increases cellular tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity. This selection process can be partially attenuated pharmacologically. Altogether, these results reveal that viral mimicry conditioning following p53 loss promotes immune evasion and may represent a pharmacological target for early cancer interception.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"35 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936209","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 : 2025-01-06DOI: 10.1158/2159-8290.cd-24-0760
Akshat Singhal, Xiaoyu Zhao, Patrick Wall, Emily So, Guido Calderini, Alexander Partin, Natasha Koussa, Priyanka Vasanthakumari, Oleksandr Narykov, Yitan Zhu, Sara E. Jones, Farnoosh Abbas-Aghababazadeh, Sisira Kadambat Nair, Jean-Christophe Bélisle-Pipon, Athmeya Jayaram, Barbara A. Parker, Kay T. Yeung, Jason I. Griffiths, Ryan Weil, Aritro Nath, Benjamin Haibe-Kains, Trey Ideker
The rapid evolution of machine learning has led to a proliferation of sophisticated models for predicting therapeutic responses in cancer. While many of these show promise in research, standards for clinical evaluation and adoption are lacking. Here, we propose seven hallmarks by which predictive oncology models can be assessed and compared. These are Data Relevance and Actionability, Expressive Architecture, Standardized Benchmarking, Generalizability, Interpretability, Accessibility and Reproducibility, and Fairness. Considerations for each hallmark are discussed along with an example model scorecard. We encourage the broader community, including researchers, clinicians, and regulators, to engage in shaping these guidelines toward a concise set of standards. Significance: As the field of artificial intelligence evolves rapidly, these hallmarks are intended to capture fundamental, complementary concepts necessary for the progress and timely adoption of predictive modeling in precision oncology. Through these hallmarks, we hope to establish standards and guidelines that enable the symbiotic development of artificial intelligence and precision oncology.
{"title":"The Hallmarks of Predictive Oncology","authors":"Akshat Singhal, Xiaoyu Zhao, Patrick Wall, Emily So, Guido Calderini, Alexander Partin, Natasha Koussa, Priyanka Vasanthakumari, Oleksandr Narykov, Yitan Zhu, Sara E. Jones, Farnoosh Abbas-Aghababazadeh, Sisira Kadambat Nair, Jean-Christophe Bélisle-Pipon, Athmeya Jayaram, Barbara A. Parker, Kay T. Yeung, Jason I. Griffiths, Ryan Weil, Aritro Nath, Benjamin Haibe-Kains, Trey Ideker","doi":"10.1158/2159-8290.cd-24-0760","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0760","url":null,"abstract":"The rapid evolution of machine learning has led to a proliferation of sophisticated models for predicting therapeutic responses in cancer. While many of these show promise in research, standards for clinical evaluation and adoption are lacking. Here, we propose seven hallmarks by which predictive oncology models can be assessed and compared. These are Data Relevance and Actionability, Expressive Architecture, Standardized Benchmarking, Generalizability, Interpretability, Accessibility and Reproducibility, and Fairness. Considerations for each hallmark are discussed along with an example model scorecard. We encourage the broader community, including researchers, clinicians, and regulators, to engage in shaping these guidelines toward a concise set of standards. Significance: As the field of artificial intelligence evolves rapidly, these hallmarks are intended to capture fundamental, complementary concepts necessary for the progress and timely adoption of predictive modeling in precision oncology. Through these hallmarks, we hope to establish standards and guidelines that enable the symbiotic development of artificial intelligence and precision oncology.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"48 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142929405","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 : 2024-12-30DOI: 10.1158/2159-8290.cd-24-0719
Jinsuke Nishino, Wenhuo Hu, Ashwin Kishtagari, Bo Shen, Xiang Gao, Caroline M. Blackman, Adetola Kassim, Naimisha Marneni, Abhisar V. Cherukuri, Russell Vittrup, Fatma N. Kalkan, Rahul Shah, Chul Ahn, Ang Gao, Abeer Ahmedrabie, Robert H. Collins, Amer M. Zeidan, Aram Bidikian, Lohith Gowda, Brian C. Shaffer, Yazan F. Madanat, Zhiyu Zhao, Stephen S. Chung, Sean J. Morrison
Peripheral nerves promote mouse bone marrow regeneration by activating b2 and b3 adrenergic receptor signaling, raising the possibility that non-selective b blockers could inhibit engraftment after hematopoietic cell transplants (HCTs). We observed no effect of b blockers on steady-state mouse hematopoiesis. However, mice treated with a non-selective b blocker (carvedilol), but not a b1-selective inhibitor (metoprolol), exhibited impaired hematopoietic regeneration after syngeneic or allogeneic HCTs. At two institutions, patients who received non-selective, but not b1-selective, b blockers after allogeneic HCT exhibited delayed platelet engraftment and reduced survival. This was particularly observed in patients who received post-transplant chemotherapy for graft-versus-host disease prophylaxis, which also accentuated the inhibitory effect of carvedilol on engraftment in mice. In patients who received autologous HCTs, non-selective b blockers were associated with little or no delay in engraftment. The inhibitory effect of non-selective b blockers after allogeneic HCT was overcome by transplanting larger doses of hematopoietic cells.
{"title":"Non-selective b adrenergic receptor inhibitors impair hematopoietic regeneration in mice and humans after hematopoietic cell transplants","authors":"Jinsuke Nishino, Wenhuo Hu, Ashwin Kishtagari, Bo Shen, Xiang Gao, Caroline M. Blackman, Adetola Kassim, Naimisha Marneni, Abhisar V. Cherukuri, Russell Vittrup, Fatma N. Kalkan, Rahul Shah, Chul Ahn, Ang Gao, Abeer Ahmedrabie, Robert H. Collins, Amer M. Zeidan, Aram Bidikian, Lohith Gowda, Brian C. Shaffer, Yazan F. Madanat, Zhiyu Zhao, Stephen S. Chung, Sean J. Morrison","doi":"10.1158/2159-8290.cd-24-0719","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0719","url":null,"abstract":"Peripheral nerves promote mouse bone marrow regeneration by activating b2 and b3 adrenergic receptor signaling, raising the possibility that non-selective b blockers could inhibit engraftment after hematopoietic cell transplants (HCTs). We observed no effect of b blockers on steady-state mouse hematopoiesis. However, mice treated with a non-selective b blocker (carvedilol), but not a b1-selective inhibitor (metoprolol), exhibited impaired hematopoietic regeneration after syngeneic or allogeneic HCTs. At two institutions, patients who received non-selective, but not b1-selective, b blockers after allogeneic HCT exhibited delayed platelet engraftment and reduced survival. This was particularly observed in patients who received post-transplant chemotherapy for graft-versus-host disease prophylaxis, which also accentuated the inhibitory effect of carvedilol on engraftment in mice. In patients who received autologous HCTs, non-selective b blockers were associated with little or no delay in engraftment. The inhibitory effect of non-selective b blockers after allogeneic HCT was overcome by transplanting larger doses of hematopoietic cells.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"41 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142904831","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 : 2024-12-20DOI: 10.1158/2159-8290.CD-24-1366
Tanjina Kader, Jia-Ren Lin, Clemens B Hug, Shannon Coy, Yu-An Chen, Ino de Bruijn, Natalie Shih, Euihye Jung, Roxanne J Pelletier, Mariana Lopez Leon, Gabriel Mingo, Dalia K Omran, Jong Suk Lee, Clarence Yapp, Baby A Satravada, Ritika Kundra, Yilin Xu, Sabrina Chan, Juliann B Tefft, Jeremy L Muhlich, Sarah H Kim, Stefan M Gysler, Judith Agudo, James R Heath, Nikolaus Schultz, Charles W Drescher, Peter K Sorger, Ronny Drapkin, Sandro Santagata
High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer.
{"title":"Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma.","authors":"Tanjina Kader, Jia-Ren Lin, Clemens B Hug, Shannon Coy, Yu-An Chen, Ino de Bruijn, Natalie Shih, Euihye Jung, Roxanne J Pelletier, Mariana Lopez Leon, Gabriel Mingo, Dalia K Omran, Jong Suk Lee, Clarence Yapp, Baby A Satravada, Ritika Kundra, Yilin Xu, Sabrina Chan, Juliann B Tefft, Jeremy L Muhlich, Sarah H Kim, Stefan M Gysler, Judith Agudo, James R Heath, Nikolaus Schultz, Charles W Drescher, Peter K Sorger, Ronny Drapkin, Sandro Santagata","doi":"10.1158/2159-8290.CD-24-1366","DOIUrl":"10.1158/2159-8290.CD-24-1366","url":null,"abstract":"<p><p>High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863423","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 : 2024-12-18DOI: 10.1158/2159-8290.cd-24-0916
Sally L. George, Claire Lynn, Reda Stankunaite, Debbie Hughes, Carolin M. Sauer, Jane Chalker, Saira Waqar Ahmed, Minou Oostveen, Paula Z. Proszek, Lina Yuan, Ridwan Shaikh, Sabri Jamal, Ama Brew, Jennifer Tall, Tony Rogers, Steven C. Clifford, Josef Vormoor, Janet M. Shipley, Deborah A. Tweddle, Chris Jones, Courtney Willis, G.A. Amos Burke, Aditi Vedi, Lisa Howell, Robert Johnston, Helen Rees, Madeleine Adams, Angela Jesudason, Milind Ronghe, Martin Elliott, Emma Ross, Guy Makin, Quentin Campbell-Hewson, Richard G. Grundy, Jennifer Turnbull, Shaun Wilson, Victoria Lee, Juliet C. Gray, Sara Stoneham, Susanne A. Gatz, Lynley V. Marshall, Paola Angelini, John Anderson, George D. Cresswell, Trevor A. Graham, Bissan Al-Lazikani, Isidro Cortes-Ciriano, Pamela Kearns, J. Ciaran Hutchinson, Darren Hargrave, Thomas S. Jacques, Michael Hubank, Andrea Sottoriva, Louis Chesler
We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived DNA (ctDNA) was present. Serial tumour sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomics analysis of cfDNA identified tumour-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intra-tumoural heterogeneity and the epigenetic state of cancer cells.
{"title":"Stratified Medicine Paediatrics: Cell free DNA and serial tumour sequencing identifies subtype specific cancer evolution and epigenetic states","authors":"Sally L. George, Claire Lynn, Reda Stankunaite, Debbie Hughes, Carolin M. Sauer, Jane Chalker, Saira Waqar Ahmed, Minou Oostveen, Paula Z. Proszek, Lina Yuan, Ridwan Shaikh, Sabri Jamal, Ama Brew, Jennifer Tall, Tony Rogers, Steven C. Clifford, Josef Vormoor, Janet M. Shipley, Deborah A. Tweddle, Chris Jones, Courtney Willis, G.A. Amos Burke, Aditi Vedi, Lisa Howell, Robert Johnston, Helen Rees, Madeleine Adams, Angela Jesudason, Milind Ronghe, Martin Elliott, Emma Ross, Guy Makin, Quentin Campbell-Hewson, Richard G. Grundy, Jennifer Turnbull, Shaun Wilson, Victoria Lee, Juliet C. Gray, Sara Stoneham, Susanne A. Gatz, Lynley V. Marshall, Paola Angelini, John Anderson, George D. Cresswell, Trevor A. Graham, Bissan Al-Lazikani, Isidro Cortes-Ciriano, Pamela Kearns, J. Ciaran Hutchinson, Darren Hargrave, Thomas S. Jacques, Michael Hubank, Andrea Sottoriva, Louis Chesler","doi":"10.1158/2159-8290.cd-24-0916","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0916","url":null,"abstract":"We profiled a large heterogenous cohort of matched diagnostic-relapse tumour tissue and paired plasma-derived cell free DNA (cfDNA) from patients with relapsed and progressive solid tumours of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intra-tumour heterogeneity captured by the latter, if sufficient circulating tumour-derived DNA (ctDNA) was present. Serial tumour sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomics analysis of cfDNA identified tumour-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intra-tumoural heterogeneity and the epigenetic state of cancer cells.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"29 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142849169","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 : 2024-12-12DOI: 10.1158/2159-8290.CD-24-0878
Taryn D Treger, Jenny Wegert, Anna Wenger, Tim H H Coorens, Reem Al-Saadi, Paul G Kemps, Jonathan Kennedy, Conor Parks, Nathaniel D Anderson, Angus Hodder, Aleksandra Letunovska, Hyunchul Jung, Toochi Ogbonnah, Mi K Trinh, Henry Lee-Six, Guillaume Morcrette, Marry M van den Heuvel-Eibrink, Jarno Drost, Ruben van Boxtel, Eline J M Bertrums, Bianca F Goemans, Evangelia Antoniou, Dirk Reinhardt, Heike Streitenberger, Barbara Ziegler, Jack Bartram, J Ciaran Hutchinson, Gordan M Vujanic, Christian Vokuhl, Tanzina Chowdhury, Rhoikos Furtwängler, Norbert Graf, Kathy Pritchard-Jones, Manfred Gessler, Sam Behjati
Ten percent of children with cancer harbour a mutation in a predisposition gene. In children with the kidney cancer, Wilms tumour, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumourigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumour, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukaemias), utilising WGS, RNA sequencing and genome wide methylation, validating our findings in an independent cohort. Tumour development differed in children harbouring a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Our findings indicate that predisposition may preordain Wilms tumourigenesis, suggesting a variant specific approach to managing children merits consideration.
{"title":"Predisposition footprints in the somatic genome of Wilms tumours.","authors":"Taryn D Treger, Jenny Wegert, Anna Wenger, Tim H H Coorens, Reem Al-Saadi, Paul G Kemps, Jonathan Kennedy, Conor Parks, Nathaniel D Anderson, Angus Hodder, Aleksandra Letunovska, Hyunchul Jung, Toochi Ogbonnah, Mi K Trinh, Henry Lee-Six, Guillaume Morcrette, Marry M van den Heuvel-Eibrink, Jarno Drost, Ruben van Boxtel, Eline J M Bertrums, Bianca F Goemans, Evangelia Antoniou, Dirk Reinhardt, Heike Streitenberger, Barbara Ziegler, Jack Bartram, J Ciaran Hutchinson, Gordan M Vujanic, Christian Vokuhl, Tanzina Chowdhury, Rhoikos Furtwängler, Norbert Graf, Kathy Pritchard-Jones, Manfred Gessler, Sam Behjati","doi":"10.1158/2159-8290.CD-24-0878","DOIUrl":"10.1158/2159-8290.CD-24-0878","url":null,"abstract":"<p><p>Ten percent of children with cancer harbour a mutation in a predisposition gene. In children with the kidney cancer, Wilms tumour, the prevalence is as high as 30%. Certain predispositions are associated with defined histological and clinical features, suggesting differences in tumourigenesis. To investigate this, we assembled a cohort of 137 children with Wilms tumour, of whom 71 had a pathogenic germline or mosaic variant. We examined 237 neoplasms (including two secondary leukaemias), utilising WGS, RNA sequencing and genome wide methylation, validating our findings in an independent cohort. Tumour development differed in children harbouring a predisposition, depending on the variant gene and its developmental timing. Differences pervaded the repertoire of driver events, including high risk mutations, the clonal architecture of normal kidneys, and the relatedness of neoplasms from the same individual. Our findings indicate that predisposition may preordain Wilms tumourigenesis, suggesting a variant specific approach to managing children merits consideration.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":""},"PeriodicalIF":29.7,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812194","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 : 2024-12-09DOI: 10.1158/2159-8290.cd-24-0559
Lisa N. Chesner, Fanny Polesso, Julie N. Graff, Jessica E. Hawley, Alexis K. Smith, Arian Lundberg, Rajdeep Das, Tanushree Shenoy, Martin Sjöström, Faming Zhao, Ya-Mei Hu, Simon Linder, William S. Chen, Reed M. Hawkins, Raunak Shrestha, Xiaolin Zhu, Adam Foye, Haolong Li, Lisa M. Kim, Megha Bhalla, Thomas O'loughlin, Duygu Kuzuoglu-Ozturk, Junjie T. Hua, Michelle L. Badura, Scott Wilkinson, Shana Y. Trostel, Andries M. Bergman, Davide Ruggero, Charles G. Drake, Adam G. Sowalsky, Lawrence Fong, Matthew R. Cooperberg, Wilbert Zwart, Xiangnan Guan, Alan Ashworth, Zheng Xia, David A. Quigley, Luke A. Gilbert, Felix Y. Feng, Amy E. Moran
Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression. To uncover the mechanism, we performed a whole genome CRISPRi screen and identified AR as a repressor of the MHCI pathway. Syngeneic mouse models of aggressive prostate cancer deficient in AR also demonstrated increased tumor immunogenicity and promoted T cell mediated tumor-control. Notably, the increase in MHCI expression upon androgen receptor blockade is transient and correlates with resistance to AR inhibition. Mechanistic studies identified androgen response elements upstream of MHCI transcription start sites which increased MHCI expression when deleted. Together, this body of work highlights another mechanism by which hormones can promote immune escape.
肿瘤通过多种机制逃避免疫检测和消灭。在这里，我们以前列腺癌为模型，研究雄激素依赖性肿瘤如何通过下调主要组织相容性复合体 I 类（MHCI）来逃避免疫。我们报告说，晚期前列腺癌对免疫疗法的反应与 MHC 表达的升高有关。为了揭示其机制，我们进行了全基因组 CRISPRi 筛选，发现 AR 是 MHCI 通路的抑制因子。缺乏AR的侵袭性前列腺癌共生小鼠模型也显示出肿瘤免疫原性增加，并促进了T细胞介导的肿瘤控制。值得注意的是，雄激素受体阻断后 MHCI 表达的增加是短暂的，并与 AR 抑制的抗性相关。机理研究发现了 MHCI 转录起始位点上游的雄激素反应元件，这些元件被删除后会增加 MHCI 的表达。这些研究成果共同强调了激素促进免疫逃逸的另一种机制。
{"title":"Androgen receptor inhibition increases MHC Class I expression and improves immune response in prostate cancer","authors":"Lisa N. Chesner, Fanny Polesso, Julie N. Graff, Jessica E. Hawley, Alexis K. Smith, Arian Lundberg, Rajdeep Das, Tanushree Shenoy, Martin Sjöström, Faming Zhao, Ya-Mei Hu, Simon Linder, William S. Chen, Reed M. Hawkins, Raunak Shrestha, Xiaolin Zhu, Adam Foye, Haolong Li, Lisa M. Kim, Megha Bhalla, Thomas O'loughlin, Duygu Kuzuoglu-Ozturk, Junjie T. Hua, Michelle L. Badura, Scott Wilkinson, Shana Y. Trostel, Andries M. Bergman, Davide Ruggero, Charles G. Drake, Adam G. Sowalsky, Lawrence Fong, Matthew R. Cooperberg, Wilbert Zwart, Xiangnan Guan, Alan Ashworth, Zheng Xia, David A. Quigley, Luke A. Gilbert, Felix Y. Feng, Amy E. Moran","doi":"10.1158/2159-8290.cd-24-0559","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0559","url":null,"abstract":"Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression. To uncover the mechanism, we performed a whole genome CRISPRi screen and identified AR as a repressor of the MHCI pathway. Syngeneic mouse models of aggressive prostate cancer deficient in AR also demonstrated increased tumor immunogenicity and promoted T cell mediated tumor-control. Notably, the increase in MHCI expression upon androgen receptor blockade is transient and correlates with resistance to AR inhibition. Mechanistic studies identified androgen response elements upstream of MHCI transcription start sites which increased MHCI expression when deleted. Together, this body of work highlights another mechanism by which hormones can promote immune escape.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"93 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142796939","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}
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