Cancer Cell最新文献

{"title":"Epidermal growth factor receptor and Ink4a/Arf: Convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis.","authors":"Robert M Bachoo, Elizabeth A Maher, Keith L Ligon, Norman E Sharpless, Suzanne S Chan, Mingjian James You, Yi Tang, Jessica DeFrances, Elizabeth Stover, Ralph Weissleder, David H Rowitch, David N Louis, Ronald A DePinho","doi":"10.1016/j.ccell.2024.11.007","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.007","url":null,"abstract":"","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"42 12","pages":"2124"},"PeriodicalIF":48.8,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142812031","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}

{"title":"Molecular subtyping in urothelial carcinoma treatment","authors":"Xiaowen Wu, Xinan Sheng","doi":"10.1016/j.ccell.2024.11.001","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.001","url":null,"abstract":"The heterogeneity of urothelial carcinoma (UC) and variable treatment responses poses significant clinical challenges. In this issue of <em>Cancer Cell</em>, Hamidi et al. conducted a multi-omics analysis of 2,803 UC patients from four clinical trials with anti-PD-L1, revealing four transcriptional subtypes. This approach could help tailor therapies for UC.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"14 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142793550","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}

{"title":"Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity","authors":"Yajing Qiu, Yapeng Su, Ermei Xie, Hongcheng Cheng, Jing Du, Yue Xu, Xiaoli Pan, Zhe Wang, Daniel G. Chen, Hong Zhu, Philip D. Greenberg, Guideng Li","doi":"10.1016/j.ccell.2024.11.003","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.003","url":null,"abstract":"Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both <em>in vitro</em> and <em>in vivo</em>. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves <em>Tcf7</em> expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, <em>in vitro</em> expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8⁺ T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"14 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776469","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}

{"title":"EZH2 inhibition enhances T cell immunotherapies by inducing lymphoma immunogenicity and improving T cell function","authors":"Yusuke Isshiki, Xi Chen, Matt Teater, Ioannis Karagiannidis, Henna Nam, Winson Cai, Cem Meydan, Min Xia, Hao Shen, Johana Gutierrez, Vigneshwari Easwar Kumar, Sebastián E. Carrasco, Madhu M. Ouseph, Samuel Yamshon, Peter Martin, Ofir Griess, Efrat Shema, Patrizia Porazzi, Marco Ruella, Renier J. Brentjens, Wendy Béguelin","doi":"10.1016/j.ccell.2024.11.006","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.11.006","url":null,"abstract":"T cell-based immunotherapies have demonstrated effectiveness in treating diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) but predicting response and understanding resistance remains a challenge. To address this, we developed syngeneic models reflecting the genetics, epigenetics, and immunology of human FL and DLBCL. We show that EZH2 inhibitors reprogram these models to re-express T cell engagement genes and render them highly immunogenic. EZH2 inhibitors do not harm tumor-controlling T cells or CAR-T cells. Instead, they reduce regulatory T cells, promote memory chimeric antigen receptor (CAR) CD8 phenotypes, and reduce exhaustion, resulting in a decreased tumor burden. Intravital 2-photon imaging shows increased CAR-T recruitment and interaction within the tumor microenvironment, improving lymphoma cell killing. Therefore, EZH2 inhibition enhances CAR-T cell efficacy through direct effects on CAR-T cells, in addition to rendering lymphoma B cells immunogenic. This approach is currently being evaluated in two clinical trials, NCT05934838 and NCT05994235, to improve immunotherapy outcomes in B cell lymphoma patients.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"222 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142776468","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}

{"title":"Interleukin-1α release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity","authors":"Kay Hänggi, Jie Li, Achintyan Gangadharan, Xiaoxian Liu, Daiana P. Celias, Olabisi Osunmakinde, Aysenur Keske, Joshua Davis, Faiz Ahmad, Auriane Giron, Carmen M. Anadon, Alycia Gardner, David G. DeNardo, Timothy I. Shaw, Amer A. Beg, Xiaoqing Yu, Brian Ruffell","doi":"10.1016/j.ccell.2024.10.014","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.014","url":null,"abstract":"Necroptosis can promote antigen-specific immune responses, suggesting induced necroptosis as a therapeutic approach for cancer. Here we sought to determine the mechanism of immune activation but found the necroptosis mediators RIPK3 and MLKL dispensable for tumor growth in genetic and implantable models of breast or lung cancer. Surprisingly, inducing necroptosis within established breast tumors generates a myeloid suppressive microenvironment that inhibits T cell function, promotes tumor growth, and reduces survival. This was dependent upon the release of the nuclear alarmin interleukin-1α (IL-1α) by dying cells. Critically, IL-1α release occurs during chemotherapy and targeting this molecule reduces the immunosuppressive capacity of tumor myeloid cells and promotes CD8⁺ T cell recruitment and effector function. Neutralizing IL-1α enhances the efficacy of single agent paclitaxel or combination therapy with PD-1 blockade in preclinical models. Low <em>IL1A</em> levels correlates with positive patient outcome in several solid malignancies, particularly in patients treated with chemotherapy.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"16 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679050","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}

{"title":"Molecular heterogeneity in urothelial carcinoma and determinants of clinical benefit to PD-L1 blockade","authors":"Habib Hamidi, Yasin Senbabaoglu, Niha Beig, Juliette Roels, Cyrus Manuel, Xiangnan Guan, Hartmut Koeppen, Zoe June Assaf, Barzin Y. Nabet, Adrian Waddell, Kobe Yuen, Sophia Maund, Ethan Sokol, Jennifer M. Giltnane, Amber Schedlbauer, Eloisa Fuentes, James D. Cowan, Edward E. Kadel, Viraj Degaonkar, Alexander Andreev-Drakhlin, Romain Banchereau","doi":"10.1016/j.ccell.2024.10.016","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.016","url":null,"abstract":"Checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have revolutionized cancer therapy across many indications including urothelial carcinoma (UC). Because many patients do not benefit, a better understanding of the molecular mechanisms underlying response and resistance is needed to improve outcomes. We profiled tumors from 2,803 UC patients from four late-stage randomized clinical trials evaluating the PD-L1 inhibitor atezolizumab by RNA sequencing (RNA-seq), a targeted DNA panel, immunohistochemistry, and digital pathology. Machine learning identifies four transcriptional subtypes, representing luminal desert, stromal, immune, and basal tumors. Overall survival benefit from atezolizumab over standard-of-care is observed in immune and basal tumors, through different response mechanisms. A self-supervised digital pathology approach can classify molecular subtypes from H&amp;E slides with high accuracy, which could accelerate tumor molecular profiling. This study represents a large integration of UC molecular and clinical data in randomized trials, paving the way for clinical studies tailoring treatment to specific molecular subtypes in UC and other indications.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"14 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679051","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}

{"title":"Mutation burden and anti-PD-1 outcomes are not universally associated with immune cell infiltration or lymphoid activation","authors":"David Hsiehchen, 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","doi":"10.1016/j.ccell.2024.10.017","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.017","url":null,"abstract":"<h2>Section snippets</h2><section><section><h2>Main text</h2>Cancers are conventionally classified as “hot” tumors that are associated with high tumor mutation burdens (TMBs) and tumor-infiltrating immune cells or “cold” tumors associated with a dearth of neoantigens and immune cell exclusion.¹ This dichotomy is frequently used to define the degree of pre-existing immune cell reactivity within the tumor microenvironment and has been linked to clinical outcomes including the efficacy of immune checkpoint inhibitor (ICI) treatment.¹ Recently,</section></section><section><section><h2>Acknowledgments</h2>D.H. is supported by a <span>Cancer Prevention and Research Institute of Texas</span> Early Clinical Investigator Award (<span>RP200549</span>) and the <span>Josephine Hughes Sterling Foundation</span>. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors received no specific funding for this work.</section></section><section><section><h2>Author contributions</h2>D.H. and H.Z. conceived the study. D.H., A.E., and J.X. performed data analyses. D.H., A.S., W.E.-D., E.S.A., S.L.G., M.J.H., H.B., D.S.B.H., S.V.L., P.C.M., R.R.M., T.W.-D., J.M., G.W.S., D.S., and H.Z. contributed to the assembly of the CARIS cohort. D.H. drafted the paper, and all authors participated in the review and editing of the manuscript.</section></section><section><section><h2>Declaration of interests</h2>A.E., J.X., G.W.S., and D.S. are employees of Caris Life Sciences.S.L.G. serves as a paid consultant/advisor to Pfizer, Daiichi Sankyo, Eli Lilly, AstraZeneca, Genentech, SeaGen, Novartis, and Menarini and has stock ownership in HCA Healthcare.E.S.A. serves as a paid consultant/advisor to Janssen, Astellas, Sanofi, Dendreon, Bayer, BMS, Amgen, Constellation, Blue Earth, Exact Sciences, Invitae, Curium, Pfizer, Merck, AstraZeneca, Clovis, and Eli Lilly; has received research support (to his</section></section>","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"41 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678574","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}

{"title":"Unraveling the tumor-initiating cells in hepatocellular carcinoma","authors":"Yu Man Tsui, Daniel Wai-Hung Ho, Irene Oi-Lin Ng","doi":"10.1016/j.ccell.2024.10.018","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.018","url":null,"abstract":"Aggressive features of hepatocellular carcinoma (HCC) are highly related to liver tumor-initiating cells (TICs), which are heterogeneous and plastic. In this issue of <em>Cancer Cell</em>, Yang et al. reveal the ability of CD49f-high TICs in shaping the tumor immunosuppressive microenvironment in HCC.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"60 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142679052","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}

{"title":"Elucidating acquired PARP inhibitor resistance in advanced prostate cancer","authors":"George Seed, Nick Beije, Wei Yuan, Claudia Bertan, Jane Goodall, Arian Lundberg, Matthew Tyler, Ines Figueiredo, Rita Pereira, Chloe Baker, Denisa Bogdan, Lewis Gallagher, Jan-Phillipp Cieslik, Semini Greening, Maryou Lambros, Rui Neves, Lorena Magraner-Pardo, Gemma Fowler, Berni Ebbs, Susana Miranda, Johann de Bono","doi":"10.1016/j.ccell.2024.10.015","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.015","url":null,"abstract":"PARP inhibition (PARPi) has anti-tumor activity against castration-resistant prostate cancer (CRPC) with homologous recombination repair (HRR) defects. However, mechanisms underlying PARPi resistance are not fully understood. While acquired mutations restoring <em>BRCA</em> genes are well documented, their clinical relevance, frequency, and mechanism of generation remain unclear. Moreover, how resistance emerges in <em>BRCA2</em> homozygously deleted (HomDel) CRPC is unknown. Evaluating samples from patients with metastatic CRPC treated in the TOPARP-B trial, we identify reversion mutations in most <em>BRCA2/PALB2</em>-mutated tumors (79%) by end of treatment. Among reversions mediated by frameshift deletions, 60% are flanked by DNA microhomologies, implicating POLQ-mediated repair. The number of reversions and time of their detection associate with radiological progression-free survival and overall survival (<em>p</em> &lt; 0.01). For <em>BRCA2</em> HomDels, selection for rare subclones without <em>BRCA2</em>-HomDel is observed following PARPi, confirmed by single circulating-tumor-cell genomics, biopsy fluorescence <em>in situ</em> hybridization (FISH), and RNA<em>ish</em>. These data support the need for restored HRR function in PARPi resistance.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"9 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142678573","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}

{"title":"Pericancerous cross-presentation to cytotoxic T lymphocytes impairs immunotherapeutic efficacy in hepatocellular carcinoma","authors":"Chun-Xiang Huang, Xiang-Ming Lao, Xu-Yan Wang, Yi-Zheng Ren, Yi-Tong Lu, Wei Shi, Ying-Zhe Wang, Cai-Yuan Wu, Li Xu, Min-Shan Chen, Qiang Gao, Lianxin Liu, Yuan Wei, Dong-Ming Kuang","doi":"10.1016/j.ccell.2024.10.012","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.012","url":null,"abstract":"Hyperprogressive disease can occur in cancer patients receiving immune checkpoint blockade (ICB) therapy, but whether and how reactive cytotoxic T lymphocytes (CTLs) exert protumorigenic effects in this context remain elusive. Herein, our study reveals that pericancerous macrophages cross-present antigens to CD103⁺ CTLs in hepatocellular carcinoma (HCC) via the endoplasmic reticulum (ER)-associated degradation machinery-mediated cytosolic pathway. This process leads to the retention of CD103⁺ CTLs in the pericancerous area, whereby they activate NLRP3 inflammasome in macrophages, promoting hepatoma progression and resistance to immunotherapy. Our single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics analysis of HCC patients shows that despite their tissue-resident effector phenotype, the aggregation of CD103⁺ CTLs predicts unfavorable clinical outcomes for HCC patients receiving multiple types of treatment. Correspondingly, therapeutic strategies that redistribute CD103⁺ CTLs can disrupt this pathogenic interplay with macrophages, enhancing the efficacy of ICB treatment against HCC.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"38 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610154","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}