Cancer Cell最新文献_第10页

Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer 人类胰腺癌中特定 KRAS 突变体的不同临床结果和生物学特征

IF 50.3 1区医学

Cancer Cell Pub Date : 2024-08-29 DOI: 10.1016/j.ccell.2024.08.002

Caitlin A. McIntyre, Adrien Grimont, Jiwoon Park, Yinuo Meng, Whitney J. Sisso, Kenneth Seier, Gun Ho Jang, Henry Walch, Victoria G. Aveson, David J. Falvo, William B. Fall, Christopher W. Chan, Andrew Wenger, Brett L. Ecker, Alessandra Pulvirenti, Rebecca Gelfer, Maria Paz Zafra, Nikolaus Schultz, Wungki Park, Eileen M. O’Reilly, Rohit Chandwani

{"title":"Distinct clinical outcomes and biological features of specific KRAS mutants in human pancreatic cancer","authors":"Caitlin A. McIntyre, Adrien Grimont, Jiwoon Park, Yinuo Meng, Whitney J. Sisso, Kenneth Seier, Gun Ho Jang, Henry Walch, Victoria G. Aveson, David J. Falvo, William B. Fall, Christopher W. Chan, Andrew Wenger, Brett L. Ecker, Alessandra Pulvirenti, Rebecca Gelfer, Maria Paz Zafra, Nikolaus Schultz, Wungki Park, Eileen M. O’Reilly, Rohit Chandwani","doi":"10.1016/j.ccell.2024.08.002","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.08.002","url":null,"abstract":"KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) are suggested to vary in oncogenicity but the implications for human patients have not been explored in depth. We examined 1,360 consecutive PDAC patients undergoing surgical resection and find that KRASG12R mutations are enriched in early-stage (stage I) disease, owing not to smaller tumor size but increased node-negativity. KRASG12R tumors are associated with decreased distant recurrence and improved survival as compared to KRASG12D. To understand the biological underpinnings, we performed spatial profiling of 20 patients and bulk RNA-sequencing of 100 tumors, finding enhanced oncogenic signaling and epithelial-mesenchymal transition (EMT) in KRASG12D and increased nuclear factor κB (NF-κB) signaling in KRASG12R tumors. Orthogonal studies of mouse KrasG12R PDAC organoids show decreased migration and improved survival in orthotopic models. KRAS alterations in PDAC are thus associated with distinct presentation, clinical outcomes, and biological behavior, highlighting the prognostic value of mutational analysis and the importance of articulating mutation-specific PDAC biology.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"57 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090447","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

Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells 抗-PD-1和抗-CTLA-4疗法联合疗法产生的克隆反应波包括祖细胞耗竭的CD8+T细胞

IF 50.3 1区医学

Cancer Cell Pub Date : 2024-08-29 DOI: 10.1016/j.ccell.2024.08.007

Kevin Wang, Paulina Coutifaris, David Brocks, Guanning Wang, Tarek Azar, Sabrina Solis, Ajeya Nandi, Shaneaka Anderson, Nicholas Han, Sasikanth Manne, Evgeny Kiner, Chirag Sachar, Minke Lucas, Sangeeth George, Patrick K. Yan, Melanie W. Kier, Amy I. Laughlin, Shawn Kothari, Josephine Giles, Divij Mathew, Alexander C. Huang

{"title":"Combination anti-PD-1 and anti-CTLA-4 therapy generates waves of clonal responses that include progenitor-exhausted CD8+ T cells","authors":"Kevin Wang, Paulina Coutifaris, David Brocks, Guanning Wang, Tarek Azar, Sabrina Solis, Ajeya Nandi, Shaneaka Anderson, Nicholas Han, Sasikanth Manne, Evgeny Kiner, Chirag Sachar, Minke Lucas, Sangeeth George, Patrick K. Yan, Melanie W. Kier, Amy I. Laughlin, Shawn Kothari, Josephine Giles, Divij Mathew, Alexander C. Huang","doi":"10.1016/j.ccell.2024.08.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.08.007","url":null,"abstract":"Combination checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies has shown promising efficacy in melanoma. However, the underlying mechanism in humans remains unclear. Here, we perform paired single-cell RNA and T cell receptor (TCR) sequencing across time in 36 patients with stage IV melanoma treated with anti-PD-1, anti-CTLA-4, or combination therapy. We develop the algorithm Cyclone to track temporal clonal dynamics and underlying cell states. Checkpoint blockade induces waves of clonal T cell responses that peak at distinct time points. Combination therapy results in greater magnitude of clonal responses at 6 and 9 weeks compared to single-agent therapies, including melanoma-specific CD8+ T cells and exhausted CD8+ T cell (TEX) clones. Focused analyses of TEX identify that anti-CTLA-4 induces robust expansion and proliferation of progenitor TEX, which synergizes with anti-PD-1 to reinvigorate TEX during combination therapy. These next generation immune profiling approaches can guide the selection of drugs, schedule, and dosing for novel combination strategies.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"379 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090513","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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Long-lasting mRNA-encoded interleukin-2 restores CD8+ T cell neoantigen immunity in MHC class I-deficient cancers 长效 mRNA 编码的白细胞介素-2 可恢复 MHC I 类缺陷癌症患者的 CD8+ T 细胞新抗原免疫力

IF 50.3 1区医学

Cancer Cell Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.010

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CCL19-producing fibroblasts promote tertiary lymphoid structure formation enhancing anti-tumor IgG response in colorectal cancer liver metastasis 产生 CCL19 的成纤维细胞可促进三级淋巴结构的形成，增强结直肠癌肝转移中的抗肿瘤 IgG 反应

IF 50.3 1区医学

Cancer Cell Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.006

{"title":"CCL19-producing fibroblasts promote tertiary lymphoid structure formation enhancing anti-tumor IgG response in colorectal cancer liver metastasis","authors":"","doi":"10.1016/j.ccell.2024.07.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.07.006","url":null,"abstract":"Tertiary lymphoid structures (TLSs) are associated with enhanced immunity in tumors. However, their formation and functions in colorectal cancer liver metastasis (CRLM) remain unclear. Here, we reveal that intra- and peri-tumor mature TLSs (TLS+) are associated with improved clinical outcomes than TLS− tumors. Using single-cell-RNA-sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we reveal that TLS+ tumors are enriched with IgG+ plasma cells (PCs), while TLS− tumors are characterized with IgA+ PCs. By generating TLS-associated PC-derived monoclonal antibodies in vitro, we show that TLS-PCs secrete tumor-targeting antibodies. As the proof-of-concept, we demonstrate the anti-tumor activities of TLS-PC-mAb6 antibody in humanized mouse model of colorectal cancer. We identify a fibroblast lineage secreting CCL19 that facilitates lymphocyte trafficking to TLSs. CCL19 treatment promotes TLS neogenesis and prevents tumor growth in mice. Our data uncover the central role of CCL19+ fibroblasts in TLS formation, which in turn generates therapeutic antibodies to restrict CRLM.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"83 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141918674","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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Development of Peptidomimetic Inhibitors of the ERG Gene Fusion Product in Prostate Cancer 开发前列腺癌 ERG 基因融合产物的拟肽抑制剂

IF 50.3 1区医学

Cancer Cell Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.009

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Integrative plasma and fecal metabolomics identify functional metabolites in adenoma-colorectal cancer progression and as early diagnostic biomarkers 整合血浆和粪便代谢组学发现腺瘤-结直肠癌进展过程中的功能代谢物和早期诊断生物标记物

IF 50.3 1区医学

Cancer Cell Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.005

引用次数: 0

Interleukin-21 engineering enhances NK cell activity against glioblastoma via CEBPD 白细胞介素-21 工程通过 CEBPD 增强 NK 细胞抗胶质母细胞瘤的活性

IF 50.3 1区医学

Cancer Cell Pub Date : 2024-08-12 DOI: 10.1016/j.ccell.2024.07.007