Cancer discovery最新文献_第10页

Evolving CAR T-Cell Therapy to Overcome the Barriers in Treating Pediatric Central Nervous System Tumors 不断发展的CAR - t细胞疗法克服治疗小儿中枢神经系统肿瘤的障碍

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-04-29 DOI: 10.1158/2159-8290.cd-24-1465

Andrea Timpanaro, Edward Z. Song, Nour Amwas, Chu-Hsuan Chiu, Rebecca Ronsley, Mallory R. Taylor, Jessica B. Foster, Leo D. Wang, Nicholas A. Vitanza

{"title":"Evolving CAR T-Cell Therapy to Overcome the Barriers in Treating Pediatric Central Nervous System Tumors","authors":"Andrea Timpanaro, Edward Z. Song, Nour Amwas, Chu-Hsuan Chiu, Rebecca Ronsley, Mallory R. Taylor, Jessica B. Foster, Leo D. Wang, Nicholas A. Vitanza","doi":"10.1158/2159-8290.cd-24-1465","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1465","url":null,"abstract":"Central nervous system (CNS) tumors are a leading cause of pediatric cancer-related death. Chimeric antigen receptor (CAR) T cells are an innovative approach for these affected children who are in desperate need of novel therapies, but CNS-directed cellular therapies have only recently advanced to the clinic. Although early-phase trials have begun to demonstrate the feasibility of manufacturing fractionated doses and the tolerability of repeated infusions for children with CNS tumors, major challenges remain. In this review, we will take an inventory of the current state of the pediatric CNS CAR T-cell field through the lens of translational obstacles to broader clinical success. Significance: CNS tumors are the leading cause of cancer-related death in children, highlighting the dire need for new treatment strategies. CAR T cells represent a unique approach, distinct from the cytotoxic chemotherapies and small-molecule inhibitors that have dominated the clinical trial space for decades. Phase I CAR T-cell trials have shown feasibility and possible efficacy against pediatric CNS tumors; however, many challenges must be overcome if these therapeutics are going to be beneficial to most affected children. Although rapid translational development and early-phase trials have quickly evolved our understanding, the pediatric CNS CAR T-cell community now yearns for critical assessments and open dialogue about overcoming the remaining obstacles ahead.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"86 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889585","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}

引用次数: 0

A RAS(ON) multi-selective inhibitor combination therapy triggers long-term tumor control through senescence-associated tumor-immune equilibrium in PDAC RAS（ON）多选择性抑制剂联合治疗通过PDAC中衰老相关的肿瘤免疫平衡触发长期肿瘤控制

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-04-29 DOI: 10.1158/2159-8290.cd-24-1425

Caroline Broderick, Riccardo Mezzadra, Exequiel M. Sisso, Felix Mbuga, Rashi Raghulan, Almudena Chaves Perez, Amanda Kulick, Lingyan Jiang, Jingjing Jiang, Yu-Jui Ho, Janelle Simon, Eric Rosiek, Eric Chan, Aveline Filliol, Ronan Chaligne, Elisa de Stanchina, Ximo Pechuan-Jorge, Andrea Schietinger, Mallika Singh, Scott W. Lowe

{"title":"A RAS(ON) multi-selective inhibitor combination therapy triggers long-term tumor control through senescence-associated tumor-immune equilibrium in PDAC","authors":"Caroline Broderick, Riccardo Mezzadra, Exequiel M. Sisso, Felix Mbuga, Rashi Raghulan, Almudena Chaves Perez, Amanda Kulick, Lingyan Jiang, Jingjing Jiang, Yu-Jui Ho, Janelle Simon, Eric Rosiek, Eric Chan, Aveline Filliol, Ronan Chaligne, Elisa de Stanchina, Ximo Pechuan-Jorge, Andrea Schietinger, Mallika Singh, Scott W. Lowe","doi":"10.1158/2159-8290.cd-24-1425","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1425","url":null,"abstract":"Pharmacological inhibition of oncogenic RAS represents an attractive strategy to target pancreatic ductal adenocarcinoma (PDAC), an almost ubiquitously RAS-driven disease. However, initial responses to targeted monotherapy inhibition of active RAS can be followed by relapses, potentially driven by the persistence of drug-tolerant tumor cells. To target these ‘persister’ cells, we investigated strategies to increase their immune visibility in mouse models of PDAC. We show that combining a RAS(ON) multi-selective inhibitor with the CDK4/6 inhibitor palbociclib drives persister cells into a senescent-like state, which coincides with improved tumor control and substantial remodeling of the tumor microenvironment. Combining RAS(ON) and CDK4/6 inhibition with a CD40 agonist results in durable regressions and CD4 T cell-dependent tumor-immune equilibrium. Our studies reveal a combinatorial approach that circumvents resistance to RAS(ON) inhibitor monotherapy in preclinical models and demonstrate a mechanism by which therapy-induced senescence can be reinforced by the immune system, resulting in durable tumor control.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"34 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889584","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}

引用次数: 0

Integrating ctDNA Analysis and Radiomics for Dynamic Risk Assessment in Localized Lung Cancer 整合ctDNA分析和放射组学用于局部肺癌的动态风险评估

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-04-29 DOI: 10.1158/2159-8290.cd-24-1704

Everett J. Moding, Mohammad Shahrokh Esfahani, Cheng Jin, Angela B. Hui, Barzin Y. Nabet, Yufei Liu, Jacob J. Chabon, Michael S. Binkley, David M. Kurtz, Emily G. Hamilton, Aadel A. Chaudhuri, Chih Long Liu, Zhe Li, Rene F. Bonilla, Alice L. Jiang, Brianna C. Lau, Pablo Lopez, Jianzhong He, Yawei Qiao, Ting Xu, Luyang Yao, Saumil Gandhi, Zhongxing Liao, Millie Das, Kavitha J. Ramchandran, Sukhmani K. Padda, Joel W. Neal, Heather A. Wakelee, Michael F. Gensheimer, Billy W. Loo, Ruijiang Li, Steven H. Lin, Ash A. Alizadeh, Maximilian Diehn

{"title":"Integrating ctDNA Analysis and Radiomics for Dynamic Risk Assessment in Localized Lung Cancer","authors":"Everett J. Moding, Mohammad Shahrokh Esfahani, Cheng Jin, Angela B. Hui, Barzin Y. Nabet, Yufei Liu, Jacob J. Chabon, Michael S. Binkley, David M. Kurtz, Emily G. Hamilton, Aadel A. Chaudhuri, Chih Long Liu, Zhe Li, Rene F. Bonilla, Alice L. Jiang, Brianna C. Lau, Pablo Lopez, Jianzhong He, Yawei Qiao, Ting Xu, Luyang Yao, Saumil Gandhi, Zhongxing Liao, Millie Das, Kavitha J. Ramchandran, Sukhmani K. Padda, Joel W. Neal, Heather A. Wakelee, Michael F. Gensheimer, Billy W. Loo, Ruijiang Li, Steven H. Lin, Ash A. Alizadeh, Maximilian Diehn","doi":"10.1158/2159-8290.cd-24-1704","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1704","url":null,"abstract":"The complementarity and clinical utility of combining liquid biopsies and radiomic image analysis has not been demonstrated. ctDNA minimal residual disease after chemoradiotherapy (CRT) for non–small cell lung cancer (NSCLC) is highly prognostic, but on-treatment biomarkers are needed to enable response-adapted therapies. In this study, we analyzed 418 patients with NSCLC undergoing CRT to develop and validate a novel dynamic risk model that accurately predicts ultimate progression-free survival during treatment. We optimize tissue-free variant calling from plasma samples to facilitate ctDNA monitoring and demonstrate the importance of accounting for persistent clonal hematopoiesis variants. We show that mid-CRT ctDNA concentration is prognostic for disease progression and integrate additional pre-CRT risk factors, including radiomics, into a combined model that improves outcome prediction. Our results suggest that tumor features, radiomics, and mid-CRT ctDNA analysis are complementary and can identify patients at high and low risk of progression to potentially enable response-adapted therapies. Significance: This study demonstrates that combining tumor features, radiomics, and ctDNA analysis improves outcome prediction in NSCLC treated with CRT therapy. Our integrated model could enable personalized and response-adapted therapies to reduce toxicity and improve outcomes in patients.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"43 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889586","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}

引用次数: 0

Detection of brain cancer using genome-wide cell-free DNA fragmentomes. 利用全基因组无细胞DNA片段组检测脑癌。

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-04-29 DOI: 10.1158/2159-8290.cd-25-0074

Dimitrios Mathios,Noushin Niknafs,Akshaya V Annapragada,Ernest J Bobeff,Elaine J Chiao,Kavya Boyapati,Keerti Boyapati,Sarah Short,Adrianna L Bartolomucci,Stephen Cristiano,Shashikant Koul,Nicholas A Vulpescu,Leonardo Ferreira,Jamie E Medina,Daniel C Bruhm,Vilmos Adleff,Małgorzata Podstawka,Patrycja Stanisławska,Chul-Kee Park,Judy Huang,Gary L Gallia,Henry Brem,Debraj Mukherjee,Justin M Caplan,Jon Weingart,Christopher M Jackson,Michael Lim,Jillian Phallen,Robert B Scharpf,Victor E Velculescu

{"title":"Detection of brain cancer using genome-wide cell-free DNA fragmentomes.","authors":"Dimitrios Mathios,Noushin Niknafs,Akshaya V Annapragada,Ernest J Bobeff,Elaine J Chiao,Kavya Boyapati,Keerti Boyapati,Sarah Short,Adrianna L Bartolomucci,Stephen Cristiano,Shashikant Koul,Nicholas A Vulpescu,Leonardo Ferreira,Jamie E Medina,Daniel C Bruhm,Vilmos Adleff,Małgorzata Podstawka,Patrycja Stanisławska,Chul-Kee Park,Judy Huang,Gary L Gallia,Henry Brem,Debraj Mukherjee,Justin M Caplan,Jon Weingart,Christopher M Jackson,Michael Lim,Jillian Phallen,Robert B Scharpf,Victor E Velculescu","doi":"10.1158/2159-8290.cd-25-0074","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0074","url":null,"abstract":"Diagnostic delays in patients with brain cancer are common and can impact patient outcome. Development of a blood-based assay for detection of brain cancers could accelerate brain cancer diagnosis. In this study, we analyzed genome-wide cell-free (cfDNA) fragmentomes, including fragmentation profiles and repeat landscapes, from the plasma of individuals with (n=148) or without (n=357) brain cancer. Machine learning analyses of cfDNA fragmentome features detected brain cancer across all grade gliomas (AUC=0.90, 95% CI: 0.87-0.93) and these results were validated in an independent prospectively collected cohort. cfDNA fragmentome changes in patients with gliomas represented a combination of fragmentation profiles from glioma cells and altered white blood cell populations in the circulation. These analyses reveal the properties of cfDNA in patients with brain cancer and open new avenues for noninvasive detection of these individuals.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"222 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143889324","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}

引用次数: 0

Response and Resistance to RAS Inhibition in Cancer 肿瘤对RAS抑制的反应和抵抗

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-04-28 DOI: 10.1158/2159-8290.cd-25-0349

Richard Y. Ebright, Julien Dilly, Alice T. Shaw, Andrew J. Aguirre

引用次数: 0

Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations 直接抑制RAS揭示RAS G12和Q61突变驱动的致癌信号传导特征

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-04-28 DOI: 10.1158/2159-8290.cd-24-0614

Michelangelo Marasco, Dinesh Kumar, Santiago Garcia Borrego, Tessa Seale, Giulia Maddalena, Riccardo Mezzadra, Kylie Belanger, Soren Cole, Brayan Perez, Wei Luan, Radha Mukherjee, Ilinca Aricescu, Vladimir Markov, Yuxin Zhu, Sabrina Arena, Alberto Bardelli, Elisa de Stanchina, Scott W. Lowe, Richard A. Burkhart, Jacquelyn W. Zimmerman, Rona Yaeger, Scott E. Kopetz, Neal Rosen, Sandra Misale

{"title":"Direct Inhibition of RAS Reveals the Features of Oncogenic Signaling Driven by RAS G12 and Q61 Mutations","authors":"Michelangelo Marasco, Dinesh Kumar, Santiago Garcia Borrego, Tessa Seale, Giulia Maddalena, Riccardo Mezzadra, Kylie Belanger, Soren Cole, Brayan Perez, Wei Luan, Radha Mukherjee, Ilinca Aricescu, Vladimir Markov, Yuxin Zhu, Sabrina Arena, Alberto Bardelli, Elisa de Stanchina, Scott W. Lowe, Richard A. Burkhart, Jacquelyn W. Zimmerman, Rona Yaeger, Scott E. Kopetz, Neal Rosen, Sandra Misale","doi":"10.1158/2159-8290.cd-24-0614","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-0614","url":null,"abstract":"RAS genes are frequently mutated in cancer, often at codons 12 and 61. With the recent introduction of RAS inhibitors, we can now directly investigate the effects of specific RAS mutations in cancer cells. In this study, we demonstrate that in tumors with RASG12X mutations, mutant RAS can be activated by receptor tyrosine kinases (RTK), and PI3K activation is dependent on mutant RAS. Conversely, RASQ61X mutations activate the MAPK cascade independently of RTKs, and inhibition of RASQ61X impairs MAPK pathway activation but leaves the PI3K pathway unaffected. Our characterization of these distinct features of G12X and Q61X mutations suggests that co-inhibition of RAS and RTKs selectively inhibits the growth of RASG12X-mutant tumors, both in vitro and in vivo, regardless of the RAS isoform and tumor type. Additionally, our findings offer a mechanistic explanation for the increased frequency of RASQ61X mutations as a secondary resistance mechanism against EGFR inhibition in colorectal cancer. Significance: RAS inhibition in multiple tumor types reveals the difference between G12 mutants and Q61 mutants in their cooperation with upstream regulators and downstream effectors to promote oncogenic signaling. Our findings provide the rationale for combinatorial approaches and contribute to explaining the nonuniform distribution of RAS mutations, de novo and at resistance.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"8 1","pages":"OF1-OF18"},"PeriodicalIF":28.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884649","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}

引用次数: 0

Intra-hepatic microbial heterogeneity in multifocal hepatocellular carcinoma and its association with host genomic and transcriptomic alterations 多灶性肝细胞癌肝内微生物异质性及其与宿主基因组和转录组改变的关系

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-04-28 DOI: 10.1158/2159-8290.cd-24-1259

Yinghong Lu, Lixia Xu, Weikang Chen, Weixin Liu, Ying Zhang, Qianying Zhou, Na Wang, Yongxin Zhang, Haojie Bai, Shu Xu, Pingmei Huang, Kaili Fu, Wenxuan Xie, Xin Liu, Xueliang Wang, Chi Chun. Wong, Ming Kuang, Jun Yu

{"title":"Intra-hepatic microbial heterogeneity in multifocal hepatocellular carcinoma and its association with host genomic and transcriptomic alterations","authors":"Yinghong Lu, Lixia Xu, Weikang Chen, Weixin Liu, Ying Zhang, Qianying Zhou, Na Wang, Yongxin Zhang, Haojie Bai, Shu Xu, Pingmei Huang, Kaili Fu, Wenxuan Xie, Xin Liu, Xueliang Wang, Chi Chun. Wong, Ming Kuang, Jun Yu","doi":"10.1158/2159-8290.cd-24-1259","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1259","url":null,"abstract":"The signature of intrahepatic microbiome in multifocal hepatocellular carcinoma (HCC) and its association with genomic alterations remain elusive. Here, we performed multi-omics profiling of 242 HCC tumor nodules and 58 adjacent non-tumor tissues from 58 multifocal HCC patients, revealing heterogeneous microbial communities in multifocal HCC. Presence of bacteria in HCC nodules was confirmed by gram-stain, LPS, LTA staining and TEM. Mutational profiling stratified patients into intrahepatic metastasis (IM)-HCC and multicentric occurrence (MO)-HCC. Bacterial communities differed between IM and MO nodules (P=0.01). A 9-bacteria biomarker panel could distinguish IM nodules from MO nodules with AUROC of 0.795. Epithelial-mesenchymal transition (EMT) pathway was up-regulated in IM nodules and correlated with IM-enriched bacteria. IM-enriched bacteria such as Enterococcus faecalis and Streptococcus anginosus promoted HCC cell migration and invasion, and tumor progression in orthotopic HCC mouse models by inducing immunosuppressive microenvironment and EMT. Collectively, intrahepatic microbiome contributes to heterogeneity and pathogenesis of multifocal HCC.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"66 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884658","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}

引用次数: 0

PLT012, a Humanized CD36-Blocking Antibody, Is Effective for Unleashing Antitumor Immunity Against Liver Cancer and Liver Metastasis 人源化cd36阻断抗体PLT012可有效释放抗肝癌和肝转移的抗肿瘤免疫

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-04-28 DOI: 10.1158/2159-8290.cd-24-1409

Sheue-Fen Tzeng, Yi-Ru Yu, Jaeoh Park, Janusz von Renesse, Huey-Wen Hsiao, Chen-Hsuan Hsu, Josep Garnica, Jintian Chen, Lu-Ting Chiu, Jonas Santol, Tse-Yu Chen, Pei-Han Chung, Lana E. Kandalaft, Patrick Starlinger, Rodney Cheng-En Hsieh, Ming-Chin Yu, Pei-Wen Hsiao, Santiago J. Carmona, Hung-Kai Chen, Zhen Meng, Yun-Han Lin, Jingying Zhou, Chin-Hsien Tsai, Ping-Chih Ho

{"title":"PLT012, a Humanized CD36-Blocking Antibody, Is Effective for Unleashing Antitumor Immunity Against Liver Cancer and Liver Metastasis","authors":"Sheue-Fen Tzeng, Yi-Ru Yu, Jaeoh Park, Janusz von Renesse, Huey-Wen Hsiao, Chen-Hsuan Hsu, Josep Garnica, Jintian Chen, Lu-Ting Chiu, Jonas Santol, Tse-Yu Chen, Pei-Han Chung, Lana E. Kandalaft, Patrick Starlinger, Rodney Cheng-En Hsieh, Ming-Chin Yu, Pei-Wen Hsiao, Santiago J. Carmona, Hung-Kai Chen, Zhen Meng, Yun-Han Lin, Jingying Zhou, Chin-Hsien Tsai, Ping-Chih Ho","doi":"10.1158/2159-8290.cd-24-1409","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-24-1409","url":null,"abstract":"Tumor cells develop various strategies to evade immune surveillance, one of which involves altering the metabolic state of the tumor microenvironment. In response to metabolic stress in the tumor microenvironment, several tumor-infiltrating immune subsets upregulate CD36 to take up lipids. This leads to impaired antitumor immunity, as intratumoral regulatory T cells exhibit increased survival and suppressive activity, whereas CD8+ T cells become more susceptible to ferroptosis and exhaustion. In this study, we develop a humanized anti-CD36 IgG4 antibody, PLT012, against the lipid-binding domain of CD36 with excellent safety and favorable pharmacokinetic features in mice and cynomolgus monkeys. PLT012 alone or in combination with PD-L1 blockade or standard-of-care immunotherapy results in robust antitumor immunity in both immunotherapy-sensitive and -resistant hepatocellular carcinomas (HCC). Notably, PLT012 also reprograms the immune landscape of human HCC ex vivo. Our findings provide proof-of-concept evidence that PLT012 reprograms antitumor immunity in HCC, positioning it as a first-in-class immunotherapy targeting CD36. Significance: Despite the success of cancer immunotherapies, like immune checkpoint inhibitors, many patients still fail to demonstrate significant responses because of metabolic constraints in tumors. PLT012 rejuvenates antitumor immunity by targeting metabolic pathways to reprogram the immune landscape of liver cancer and liver metastasis, with potential to influence future HCC immunotherapy.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"37 1","pages":"OF1-OF21"},"PeriodicalIF":28.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884646","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}

引用次数: 0

Mutant p53 Gain of Function: Why Many See It, Why Some Do not 突变型p53功能的获得：为什么很多人看到，为什么有些人看不到

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-04-27 DOI: 10.1158/2159-8290.cd-24-1638

Guillermina Lozano, Carol Prives, Kanaga Sabapathy

引用次数: 0

HPV16-Expressing Tumors Release Multiple IL-1 Ligands to Orchestrate Systemic Immunosuppression Whose Disruption Enables Efficacy of a Therapeutic Vaccine 表达hpv16的肿瘤释放多种IL-1配体来协调全身免疫抑制，其破坏使治疗性疫苗有效

IF 28.2 1区医学

Cancer discovery Pub Date : 2025-04-27 DOI: 10.1158/2159-8290.cd-25-0382

Morgane Lecointre, Jérémy Guillot, Rachel Marcone, Dilara Ozdoganlar, Marjorie Cayatte, Elin Jaensson Gyllenbäck, David Liberg, Nadine Fournier, Krisztian Homicsko, Douglas Hanahan

{"title":"HPV16-Expressing Tumors Release Multiple IL-1 Ligands to Orchestrate Systemic Immunosuppression Whose Disruption Enables Efficacy of a Therapeutic Vaccine","authors":"Morgane Lecointre, Jérémy Guillot, Rachel Marcone, Dilara Ozdoganlar, Marjorie Cayatte, Elin Jaensson Gyllenbäck, David Liberg, Nadine Fournier, Krisztian Homicsko, Douglas Hanahan","doi":"10.1158/2159-8290.cd-25-0382","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-0382","url":null,"abstract":"It is well-established that symptomatic cancers evade immune destruction by coalescing tumor microenvironments to suppress adaptive immunity. Additionally, mouse models of cervical and other cancers have revealed a capability of tumors to systemically induce the expansion of neutrophils that cripple T-cell development in spleen and lymph nodes, further impairing immune responses. Now we show that human papillomavirus type 16 (HPV16)–driven squamous cell tumors in the cervix and skin release into the circulatory system four immunoregulatory ligands – IL-1α, IL-1β, IL-33, and IL-36β – that bias the bone marrow toward granulocytic myelopoiesis, producing immunosuppressive neutrophils populating spleens and tumors. An IL-1 family coreceptor antagonist, anti-IL1RAP, abrogates this neutrophil expansion and complements an otherwise inefficacious HPV16 E7 peptide vaccine to elicit an effective antitumor immune response that is further sustained by anti–CTLA-4. Evidence for similarly IL-1–driven systemic immunosuppression in human cervical tumors encourages evaluation of this combinatorial therapeutic strategy for treating a largely immunoevasive cancer type. Significance: Cervical cancer is the fourth leading cause of cancer deaths in women worldwide. Although the disease is driven by two antigenic viral oncoproteins, therapeutic vaccines have proved ineffective, inferentially due to systemic immunosuppression. This study elucidated an actionable mechanism, whose disruption renders an oncoprotein vaccine efficacious, with translational potential.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"84 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143880659","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}

引用次数: 0