Pub Date : 2024-11-21DOI: 10.1016/j.ccell.2024.10.014
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
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 IL1A levels correlates with positive patient outcome in several solid malignancies, particularly in patients treated with chemotherapy.
坏死可以促进抗原特异性免疫反应，这表明诱导坏死是一种治疗癌症的方法。在这里，我们试图确定免疫激活的机制，但发现在乳腺癌或肺癌的遗传和植入模型中，坏死介质RIPK3和MLKL对肿瘤生长是不可或缺的。令人惊讶的是，在已确立的乳腺肿瘤中诱导坏死生成会产生一种骨髓抑制性微环境，从而抑制 T 细胞功能、促进肿瘤生长并降低存活率。这依赖于死亡细胞释放的核警报素白细胞介素-1α（IL-1α）。重要的是，IL-1α会在化疗期间释放，而靶向这一分子可降低肿瘤髓系细胞的免疫抑制能力，促进CD8+ T细胞的募集和效应功能。在临床前模型中，中和 IL-1α 可增强单药紫杉醇或与 PD-1 阻断剂联合治疗的疗效。在几种实体恶性肿瘤中，低IL1A水平与患者的预后相关，尤其是在接受化疗的患者中。
{"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<sup>+</sup> 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}
Pub Date : 2024-11-21DOI: 10.1016/j.ccell.2024.10.016
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
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&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.
{"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&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}
Pub Date : 2024-11-21DOI: 10.1016/j.ccell.2024.10.017
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
Section snippets
Main text
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,
Acknowledgments
D.H. is supported by a Cancer Prevention and Research Institute of Texas Early Clinical Investigator Award (RP200549) and the Josephine Hughes Sterling Foundation. 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.
Author contributions
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.
Declaration of interests
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
{"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.<sup>1</sup> 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.<sup>1</sup> 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}
Pub Date : 2024-11-21DOI: 10.1016/j.ccell.2024.10.018
Yu Man Tsui, Daniel Wai-Hung Ho, Irene Oi-Lin Ng
Aggressive features of hepatocellular carcinoma (HCC) are highly related to liver tumor-initiating cells (TICs), which are heterogeneous and plastic. In this issue of Cancer Cell, Yang et al. reveal the ability of CD49f-high TICs in shaping the tumor immunosuppressive microenvironment in HCC.
{"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}
Pub Date : 2024-11-21DOI: 10.1016/j.ccell.2024.10.015
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
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 BRCA genes are well documented, their clinical relevance, frequency, and mechanism of generation remain unclear. Moreover, how resistance emerges in BRCA2 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 BRCA2/PALB2-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 (p < 0.01). For BRCA2 HomDels, selection for rare subclones without BRCA2-HomDel is observed following PARPi, confirmed by single circulating-tumor-cell genomics, biopsy fluorescence in situ hybridization (FISH), and RNAish. These data support the need for restored HRR function in PARPi resistance.
{"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> < 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}
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.
{"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<sup>+</sup> CTLs in hepatocellular carcinoma (HCC) via the endoplasmic reticulum (ER)-associated degradation machinery-mediated cytosolic pathway. This process leads to the retention of CD103<sup>+</sup> 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<sup>+</sup> CTLs predicts unfavorable clinical outcomes for HCC patients receiving multiple types of treatment. Correspondingly, therapeutic strategies that redistribute CD103<sup>+</sup> 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}
Pub Date : 2024-11-14DOI: 10.1016/j.ccell.2024.10.011
Lara Haase, Christian Frezza
Itaconate is a metabolite produced by macrophages upon infection and acts as an antimicrobial molecule. In this issue of Cancer Cell, Lin et al. found that itaconate produced by tumor-associated macrophages is taken up by cancer cells via the transporter solute carrier family 13 member 3 (SLC13A3), promoting resistance to immune checkpoint inhibitors.
{"title":"Itaconate promotes an unexpected tumor immune escape mechanism","authors":"Lara Haase, Christian Frezza","doi":"10.1016/j.ccell.2024.10.011","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.011","url":null,"abstract":"Itaconate is a metabolite produced by macrophages upon infection and acts as an antimicrobial molecule. In this issue of <em>Cancer Cell</em>, Lin et al. found that itaconate produced by tumor-associated macrophages is taken up by cancer cells via the transporter solute carrier family 13 member 3 (SLC13A3), promoting resistance to immune checkpoint inhibitors.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"20 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610083","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 : 2024-11-11DOI: 10.1016/j.ccell.2024.10.009
Robert L. Bowman, Andrew J. Dunbar, Tanmay Mishra, Wenbin Xiao, Michael R. Waarts, Inés Fernández Maestre, Shira E. Eisman, Louise Cai, Shoron Mowla, Nisargbhai Shah, Angela Youn, Laura Bennett, Suean Fontenard, Shreeya Gounder, Anushka Gandhi, Michael Bowman, Kavi O’Connor, Zachary Zaroogian, Pablo Sánchez-Vela, Anthony R. Martinez Benitez, Ross L. Levine
Cancer evolution is a multifaceted process leading to dysregulation of cellular expansion and differentiation through somatic mutations and epigenetic dysfunction. Clonal expansion and evolution is driven by cell-intrinsic and -extrinsic selective pressures, which can be captured with increasing resolution by single-cell and bulk DNA sequencing. Despite the extensive genomic alterations revealed in profiling studies, there remain limited experimental systems to model and perturb evolutionary processes. Here, we integrate multi-recombinase tools for reversible, sequential mutagenesis from premalignancy to leukemia. We demonstrate that inducible Flt3 mutations differentially cooperate with Dnmt3a, Idh2, and Npm1 mutant alleles, and that changing the order of mutations influences cellular and transcriptional landscapes. We next use a generalizable, reversible approach to demonstrate that mutation reversion results in rapid leukemic regression with distinct differentiation patterns depending upon co-occurring mutations. These studies provide a path to experimentally model sequential mutagenesis, investigate mechanisms of transformation and probe oncogenic dependency in disease evolution.
{"title":"In vivo models of subclonal oncogenesis and dependency in hematopoietic malignancy","authors":"Robert L. Bowman, Andrew J. Dunbar, Tanmay Mishra, Wenbin Xiao, Michael R. Waarts, Inés Fernández Maestre, Shira E. Eisman, Louise Cai, Shoron Mowla, Nisargbhai Shah, Angela Youn, Laura Bennett, Suean Fontenard, Shreeya Gounder, Anushka Gandhi, Michael Bowman, Kavi O’Connor, Zachary Zaroogian, Pablo Sánchez-Vela, Anthony R. Martinez Benitez, Ross L. Levine","doi":"10.1016/j.ccell.2024.10.009","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.009","url":null,"abstract":"Cancer evolution is a multifaceted process leading to dysregulation of cellular expansion and differentiation through somatic mutations and epigenetic dysfunction. Clonal expansion and evolution is driven by cell-intrinsic and -extrinsic selective pressures, which can be captured with increasing resolution by single-cell and bulk DNA sequencing. Despite the extensive genomic alterations revealed in profiling studies, there remain limited experimental systems to model and perturb evolutionary processes. Here, we integrate multi-recombinase tools for reversible, sequential mutagenesis from premalignancy to leukemia. We demonstrate that inducible <em>Flt3</em> mutations differentially cooperate with <em>Dnmt3a</em>, <em>Idh2</em>, and <em>Npm1</em> mutant alleles, and that changing the order of mutations influences cellular and transcriptional landscapes. We next use a generalizable, reversible approach to demonstrate that mutation reversion results in rapid leukemic regression with distinct differentiation patterns depending upon co-occurring mutations. These studies provide a path to experimentally model sequential mutagenesis, investigate mechanisms of transformation and probe oncogenic dependency in disease evolution.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"41 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599558","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 : 2024-11-11DOI: 10.1016/j.ccell.2024.10.013
Rei Kudo, Anton Safonov, Catherine Jones, Enrico Moiso, Jonathan R. Dry, Hong Shao, Sharanya Nag, Edaise M. da Silva, Selma Yeni Yildirim, Qing Li, Elizabeth O’Connell, Payal Patel, Marie Will, Atsushi Fushimi, Marimar Benitez, Martina Bradic, Li Fan, Harikrishna Nakshatri, Dhivya R. Sudhan, Christopher R. Denz, Sarat Chandarlapaty
(Cancer Cell 42, 1919–1935.e9; November 11, 2024)
(癌症细胞》第 42 期，1919-1935.e9；2024 年 11 月 11 日）
{"title":"Long-term breast cancer response to CDK4/6 inhibition defined by TP53-mediated geroconversion","authors":"Rei Kudo, Anton Safonov, Catherine Jones, Enrico Moiso, Jonathan R. Dry, Hong Shao, Sharanya Nag, Edaise M. da Silva, Selma Yeni Yildirim, Qing Li, Elizabeth O’Connell, Payal Patel, Marie Will, Atsushi Fushimi, Marimar Benitez, Martina Bradic, Li Fan, Harikrishna Nakshatri, Dhivya R. Sudhan, Christopher R. Denz, Sarat Chandarlapaty","doi":"10.1016/j.ccell.2024.10.013","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.013","url":null,"abstract":"(Cancer Cell <em>42</em>, 1919–1935.e9; November 11, 2024)","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"61 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599559","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 : 2024-11-07DOI: 10.1016/j.ccell.2024.10.008
Chen Yang, Haigang Geng, Xupeng Yang, Shuyi Ji, Zhicheng Liu, Hao Feng, Qian Li, Tangansu Zhang, Sisi Zhang, Xuhui Ma, Chuchen Zhu, Nuo Xu, Yuhan Xia, Yan Li, Hongye Wang, Chune Yu, Shangce Du, Beiping Miao, Lei Xu, Hui Wang, Cun Wang
Tumor-initiating cells (TICs) possess the ability to evade anti-tumor immunity, potentially explaining many failures of cancer immunotherapy. Here, we identify CD49f as a prominent marker for discerning TICs in hepatocellular carcinoma (HCC), outperforming other commonly used TIC markers. CD49f-high TICs specifically recruit tumor-promoting neutrophils via the CXCL2-CXCR2 axis and create an immunosuppressive milieu in the tumor microenvironment (TME). Reciprocally, the neutrophils reprogram nearby tumor cells toward a TIC phenotype via secreting CCL4. These cells can evade CD8+ T cell-mediated killing through CCL4/STAT3-induced and CD49f-stabilized CD155 expression. Notably, while aberrant CD155 expression contributes to immune suppression, it also represents a TIC-specific vulnerability. We demonstrate that either CD155 deletion or antibody blockade significantly enhances sensitivity to anti-PD-1 therapy in preclinical HCC models. Our findings reveal a new mechanism of tumor immune evasion and provide a rationale for combining CD155 blockade with anti-PD-1/PD-L1 therapy in HCC.
{"title":"Targeting the immune privilege of tumor-initiating cells to enhance cancer immunotherapy","authors":"Chen Yang, Haigang Geng, Xupeng Yang, Shuyi Ji, Zhicheng Liu, Hao Feng, Qian Li, Tangansu Zhang, Sisi Zhang, Xuhui Ma, Chuchen Zhu, Nuo Xu, Yuhan Xia, Yan Li, Hongye Wang, Chune Yu, Shangce Du, Beiping Miao, Lei Xu, Hui Wang, Cun Wang","doi":"10.1016/j.ccell.2024.10.008","DOIUrl":"https://doi.org/10.1016/j.ccell.2024.10.008","url":null,"abstract":"Tumor-initiating cells (TICs) possess the ability to evade anti-tumor immunity, potentially explaining many failures of cancer immunotherapy. Here, we identify CD49f as a prominent marker for discerning TICs in hepatocellular carcinoma (HCC), outperforming other commonly used TIC markers. CD49f-high TICs specifically recruit tumor-promoting neutrophils via the CXCL2-CXCR2 axis and create an immunosuppressive milieu in the tumor microenvironment (TME). Reciprocally, the neutrophils reprogram nearby tumor cells toward a TIC phenotype via secreting CCL4. These cells can evade CD8<sup>+</sup> T cell-mediated killing through CCL4/STAT3-induced and CD49f-stabilized CD155 expression. Notably, while aberrant CD155 expression contributes to immune suppression, it also represents a TIC-specific vulnerability. We demonstrate that either CD155 deletion or antibody blockade significantly enhances sensitivity to anti-PD-1 therapy in preclinical HCC models. Our findings reveal a new mechanism of tumor immune evasion and provide a rationale for combining CD155 blockade with anti-PD-1/PD-L1 therapy in HCC.","PeriodicalId":9670,"journal":{"name":"Cancer Cell","volume":"92 1","pages":""},"PeriodicalIF":50.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142594595","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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