Viviana Rubino, Michelle Hüppi, Sabine Höpner, Luigi Tortola, Noah Schnüriger, Hugo Legenne, Lea Taylor, Svenja Voggensperger, Irene Keller, Remy Bruggman, Marie-Noëlle Kronig, Ulrike Bacher, Manfred Kopf, Adrian F Ochsenbein, Carsten Riether
{"title":"IL-21/IL-21R signaling renders acute myeloid leukemia stem cells more susceptible to cytarabine treatment and CAR T cell therapy.","authors":"Viviana Rubino, Michelle Hüppi, Sabine Höpner, Luigi Tortola, Noah Schnüriger, Hugo Legenne, Lea Taylor, Svenja Voggensperger, Irene Keller, Remy Bruggman, Marie-Noëlle Kronig, Ulrike Bacher, Manfred Kopf, Adrian F Ochsenbein, Carsten Riether","doi":"10.1016/j.xcrm.2024.101826","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101826","url":null,"abstract":"<p><p>Self-renewal programs in leukemia stem cells (LSCs) predict poor prognosis in patients with acute myeloid leukemia (AML). We identify CD4<sup>+</sup> T cell-derived interleukin (IL)-21 as an important negative regulator of self-renewal of LSCs. IL-21/IL-21R signaling favors asymmetric cell division and differentiation in LSCs through the activation of p38-MAPK signaling, resulting in reduced LSC numbers and significantly prolonged survival in murine AML models. In human AML, serum IL-21 at diagnosis is identified as an independent positive prognostic biomarker for outcome and correlates with improved survival and higher complete remission rates in patients that underwent high-dose chemotherapy. IL-21 treatment inhibits primary LSC function and enhances the effect of cytarabine and CD70 CAR T cell treatment on LSCs in vitro. Low-dose IL-21 treatment prolongs the survival of AML mice in syngeneic and xenograft experiments. Therefore, promoting IL-21/IL-21R signaling on LSCs may be an approach to reduce stemness and increase differentiation in AML.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101826"},"PeriodicalIF":11.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615482","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}
Lucrezia Della Volpe, Federico Midena, Roberta Vacca, Teresa Tavella, Laura Alessandrini, Giacomo Farina, Chiara Brandas, Elena Lo Furno, Kety Giannetti, Edoardo Carsana, Matteo M Naldini, Matteo Barcella, Samuele Ferrari, Stefano Beretta, Antonella Santoro, Simona Porcellini, Angelica Varesi, Diego Gilioli, Anastasia Conti, Ivan Merelli, Bernhard Gentner, Anna Villa, Luigi Naldini, Raffaella Di Micco
{"title":"A p38 MAPK-ROS axis fuels proliferation stress and DNA damage during CRISPR-Cas9 gene editing in hematopoietic stem and progenitor cells.","authors":"Lucrezia Della Volpe, Federico Midena, Roberta Vacca, Teresa Tavella, Laura Alessandrini, Giacomo Farina, Chiara Brandas, Elena Lo Furno, Kety Giannetti, Edoardo Carsana, Matteo M Naldini, Matteo Barcella, Samuele Ferrari, Stefano Beretta, Antonella Santoro, Simona Porcellini, Angelica Varesi, Diego Gilioli, Anastasia Conti, Ivan Merelli, Bernhard Gentner, Anna Villa, Luigi Naldini, Raffaella Di Micco","doi":"10.1016/j.xcrm.2024.101823","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101823","url":null,"abstract":"<p><p>Ex vivo activation is a prerequisite to reaching adequate levels of gene editing by homology-directed repair (HDR) for hematopoietic stem and progenitor cell (HSPC)-based clinical applications. Here, we show that shortening culture time mitigates the p53-mediated DNA damage response to CRISPR-Cas9-induced DNA double-strand breaks, enhancing the reconstitution capacity of edited HSPCs. However, this results in lower HDR efficiency, rendering ex vivo culture necessary yet detrimental. Mechanistically, ex vivo activation triggers a multi-step process initiated by p38 mitogen-activated protein kinase (MAPK) phosphorylation, which generates mitogenic reactive oxygen species (ROS), promoting fast cell-cycle progression and subsequent proliferation-induced DNA damage. Thus, p38 inhibition before gene editing delays G1/S transition and expands transcriptionally defined HSCs, ultimately endowing edited cells with superior multi-lineage differentiation, persistence throughout serial transplantation, enhanced polyclonal repertoire, and better-preserved genome integrity. Our data identify proliferative stress as a driver of HSPC dysfunction with fundamental implications for designing more effective and safer gene correction strategies for clinical applications.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101823"},"PeriodicalIF":11.7,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615473","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":"Probiotics and their metabolite spermidine enhance IFN-γ<sup>+</sup>CD4<sup>+</sup> T cell immunity to inhibit hepatitis B virus.","authors":"Tixiao Wang, Yuchen Fan, Siyu Tan, Zehua Wang, Mengzhen Li, Xiaowei Guo, Xiangguo Yu, Qinghai Lin, Xiaojia Song, Leiqi Xu, Lixiang Li, Shiyang Li, Lifen Gao, Xiaohong Liang, Chunyang Li, Chunhong Ma","doi":"10.1016/j.xcrm.2024.101822","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101822","url":null,"abstract":"<p><p>The therapeutic potential of commensal microbes and their metabolites is promising in the functional cure of chronic hepatitis B virus (HBV) infection, which is defined as hepatitis B surface antigen (HBsAg) loss. Here, using both specific-pathogen-free and germ-free mice, we report that probiotics significantly promote the decline of HBsAg and inhibit HBV replication by enhancing intestinal homeostasis and provoking intrahepatic interferon (IFN)-γ<sup>+</sup>CD4<sup>+</sup> T cell immune response. Depletion of CD4<sup>+</sup> T cells or blockage of IFN-γ abolishes probiotics-mediated HBV inhibition. Specifically, probiotics-derived spermidine accumulates in the gut and transports to the liver, where it exhibits a similar anti-HBV effect. Mechanistically, spermidine enhances IFN-γ<sup>+</sup>CD4<sup>+</sup> T cell immunity by autophagy. Strikingly, administration of probiotics in HBV patients reveals a preliminary trend to accelerate the decline of serum HBsAg. In conclusion, probiotics and their derived spermidine promote HBV clearance via autophagy-enhanced IFN-γ<sup>+</sup>CD4<sup>+</sup> T cell immunity, highlighting the therapeutic potential of probiotics and spermidine for the functional cure of HBV patients.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101822"},"PeriodicalIF":11.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615489","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}
Karen Minassian, Brigitta Freundl, Peter Lackner, Ursula S Hofstoetter
{"title":"Transcutaneous spinal cord stimulation neuromodulates pre- and postsynaptic inhibition in the control of spinal spasticity.","authors":"Karen Minassian, Brigitta Freundl, Peter Lackner, Ursula S Hofstoetter","doi":"10.1016/j.xcrm.2024.101805","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101805","url":null,"abstract":"<p><p>Aside from enabling voluntary control over paralyzed muscles, a key effect of spinal cord stimulation is the alleviation of spasticity. Dysfunction of spinal inhibitory circuits is considered a major cause of spasticity. These circuits are contacted by Ia muscle spindle afferents, which are also the primary targets of transcutaneous lumbar spinal cord stimulation (TSCS). We hypothesize that TSCS controls spasticity by transiently strengthening spinal inhibitory circuit function through their Ia-mediated activation. We show that 30 min of antispasticity TSCS improves activity in post- and presynaptic inhibitory circuits beyond the intervention in ten individuals with traumatic spinal cord injury to normative levels established in 20 neurologically intact individuals. These changes in circuit function correlate with improvements in muscle hypertonia, spasms, and clonus. Our study opens the black box of the carryover effects of antispasticity TSCS and underpins a causal role of deficient post- and presynaptic inhibitory circuits in spinal spasticity.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101805"},"PeriodicalIF":11.7,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615567","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}
Yiqian Gu, Ann Ly, Sara Rodriguez, Hanwei Zhang, Jiyoon Kim, Zhiyuan Mao, Ankush Sachdeva, Nazy Zomorodian, Matteo Pellegrini, Gang Li, Sandy Liu, Alexandra Drakaki, Matthew B Rettig, Arnold I Chin
{"title":"PD-1 blockade plus cisplatin-based chemotherapy in patients with small cell/neuroendocrine bladder and prostate cancers.","authors":"Yiqian Gu, Ann Ly, Sara Rodriguez, Hanwei Zhang, Jiyoon Kim, Zhiyuan Mao, Ankush Sachdeva, Nazy Zomorodian, Matteo Pellegrini, Gang Li, Sandy Liu, Alexandra Drakaki, Matthew B Rettig, Arnold I Chin","doi":"10.1016/j.xcrm.2024.101824","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101824","url":null,"abstract":"<p><p>Small cell neuroendocrine cancers share biologic similarities across tissue types, including transient response to platinum-based chemotherapy with rapid progression of disease. We report a phase 1b study of pembrolizumab in combination with platinum-based chemotherapy in 15 patients with stage III-IV small cell bladder (cohort 1) or small cell/neuroendocrine prostate cancers (cohort 2). Overall response rate (ORR) is 43% with two-year overall survival (OS) rate of 86% (95% confidence interval [CI]: 0.63, 1.00) for cohort 1 and 57% (95% CI: 0.30, 1.00) for cohort 2. Treatment is tolerated well with grade 3 or higher adverse events occurring in 40% of patients with no deaths or treatment cessation secondary to toxicity. Single-cell and T cell receptor sequencing of serial peripheral blood samples reveals clonal expansion of diverse T cell repertoire correlating with progression-free survival. Our results demonstrate promising efficacy and safety of this treatment combination and support future investigation of this biomarker. This study was registered at ClinicalTrials.gov (NCT03582475).</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101824"},"PeriodicalIF":11.7,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615486","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":"Discovery of biophysical rate laws from the electronic health record enables real-time liver injury estimation from transaminase dynamics.","authors":"Marc S Sherman, Wolfram Goessling","doi":"10.1016/j.xcrm.2024.101828","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101828","url":null,"abstract":"<p><p>Alanine (ALT) and aspartate (AST) aminotransferases are standard-of-care biomarkers for liver injury though their temporal dynamics during injury and resolution remain incompletely characterized. Here, we analyze aminotransferase kinetics to determine whether rate laws can be ascertained during acute liver injury agnostic to etiology. From 6.5 million AST and ALT measurements in 91,086 patients, we identify a single rate-limiting step in transaminase decline enabling the discovery of plasma clearance rates of AST (1.13 days<sup>-1</sup>) and ALT (0.47 days<sup>-1</sup>). These rates highlight that transaminases lag real-time liver injury on timescales relevant to clinical decision-making. To resolve this delay, we introduce a correction for AST and ALT, the hepatocyte injury index (HIX, hix.massgeneral.org), which yields a real-time estimate of liver injury. For both liver biopsies and choledocholithiasis, the HIX better distinguishes persistent versus resolved liver injury than transaminase values alone. The HIX can enable more timely clinical decisions for patients with acute liver injury.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101828"},"PeriodicalIF":11.7,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615478","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}
Jaesik Kim, Matei Ionita, Matthew Lee, Michelle L McKeague, Ajinkya Pattekar, Mark M Painter, Joost Wagenaar, Van Truong, Dylan T Norton, Divij Mathew, Yonghyun Nam, Sokratis A Apostolidis, Cynthia Clendenin, Patryk Orzechowski, Sang-Hyuk Jung, Jakob Woerner, Caroline A G Ittner, Alexandra P Turner, Mika Esperanza, Thomas G Dunn, Nilam S Mangalmurti, John P Reilly, Nuala J Meyer, Carolyn S Calfee, Kathleen D Liu, Michael A Matthy, Lamorna Brown Swigart, Ellen L Burnham, Jeffrey McKeehan, Sheetal Gandotra, Derek W Russel, Kevin W Gibbs, Karl W Thomas, Harsh Barot, Allison R Greenplate, E John Wherry, Dokyoon Kim
{"title":"Cytometry masked autoencoder: An accurate and interpretable automated immunophenotyper.","authors":"Jaesik Kim, Matei Ionita, Matthew Lee, Michelle L McKeague, Ajinkya Pattekar, Mark M Painter, Joost Wagenaar, Van Truong, Dylan T Norton, Divij Mathew, Yonghyun Nam, Sokratis A Apostolidis, Cynthia Clendenin, Patryk Orzechowski, Sang-Hyuk Jung, Jakob Woerner, Caroline A G Ittner, Alexandra P Turner, Mika Esperanza, Thomas G Dunn, Nilam S Mangalmurti, John P Reilly, Nuala J Meyer, Carolyn S Calfee, Kathleen D Liu, Michael A Matthy, Lamorna Brown Swigart, Ellen L Burnham, Jeffrey McKeehan, Sheetal Gandotra, Derek W Russel, Kevin W Gibbs, Karl W Thomas, Harsh Barot, Allison R Greenplate, E John Wherry, Dokyoon Kim","doi":"10.1016/j.xcrm.2024.101808","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101808","url":null,"abstract":"<p><p>Single-cell cytometry data are crucial for understanding the role of the immune system in diseases and responses to treatment. However, traditional methods for annotating cytometry data face challenges in scalability, robustness, and accuracy. We propose a cytometry masked autoencoder (cyMAE), which automates immunophenotyping tasks including cell type annotation. The model upholds user-defined cell type definitions, facilitating interpretability and cross-study comparisons. The training of cyMAE has a self-supervised phase, which leverages large amounts of unlabeled data, followed by fine-tuning on specialized tasks using smaller amounts of annotated data. The cost of training a new model is amortized over repeated inferences on new datasets using the same panel. Through validation across multiple studies using the same panel, we demonstrate that cyMAE delivers accurate and interpretable cellular immunophenotyping and improves the prediction of subject-level metadata. This proof of concept marks a significant step forward for large-scale immunology studies.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101808"},"PeriodicalIF":11.7,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602656","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}
Michael J Campbell, Denise M Wolf, Christina Yau, Lamorna Brown-Swigart, Julie Wulfkuhle, Isela R Gallagher, Zelos Zhu, Jennifer Bolen, Scott Vandenberg, Clifford Hoyt, Hidetoshi Mori, Alexander Borowsky, Laura Sit, Jane Perlmutter, Smita M Asare, Rita Nanda, Minetta C Liu, Douglas Yee, Angela M DeMichele, Nola M Hylton, Lajos Pusztai, Donald A Berry, Gillian L Hirst, Emanuel F Petricoin, Laura Van't Veer, Laura Esserman
{"title":"Multi-platform biomarkers of response to an immune checkpoint inhibitor in the neoadjuvant I-SPY 2 trial for early-stage breast cancer.","authors":"Michael J Campbell, Denise M Wolf, Christina Yau, Lamorna Brown-Swigart, Julie Wulfkuhle, Isela R Gallagher, Zelos Zhu, Jennifer Bolen, Scott Vandenberg, Clifford Hoyt, Hidetoshi Mori, Alexander Borowsky, Laura Sit, Jane Perlmutter, Smita M Asare, Rita Nanda, Minetta C Liu, Douglas Yee, Angela M DeMichele, Nola M Hylton, Lajos Pusztai, Donald A Berry, Gillian L Hirst, Emanuel F Petricoin, Laura Van't Veer, Laura Esserman","doi":"10.1016/j.xcrm.2024.101799","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101799","url":null,"abstract":"<p><p>Only a subset of patients with breast cancer responds to immune checkpoint blockade (ICB). To better understand the underlying mechanisms, we analyze pretreatment biopsies from patients in the I-SPY 2 trial who receive neoadjuvant ICB using multiple platforms to profile the tumor microenvironment. A variety of immune cell populations and markers of immune/cytokine signaling associate with pathologic complete response (pCR). Interestingly, these differ by breast cancer receptor subtype. Measures of the spatial distributions of immune cells within the tumor microenvironment, in particular colocalization or close spatial proximity of PD-1<sup>+</sup> T cells with PD-L1<sup>+</sup> cells (immune and tumor cells), are significantly associated with response in the overall cohort as well as the in the triple negative (TN) and HR<sup>+</sup>HER2<sup>-</sup> subtypes. Our findings indicate that biomarkers associated with immune cell signaling, immune cell densities, and spatial metrics are predictive of neoadjuvant ICB efficacy in breast cancer.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101799"},"PeriodicalIF":11.7,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602819","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}
Chang Gong, Yuan Xia, Yingying Zhu, Yaping Yang, Qun Lin, Qiang Liu, Wenqian Yang, Li Ling, Jiajie Zhong, Zhuxi Duan, Yunjie Zeng, Ziliang Cheng, Jun Shen, Yinduo Zeng, Louis Wing Cheong Chow, Erwei Song
{"title":"Preclinical study and phase 2 trial of neoadjuvant pyrotinib combined with chemotherapy in luminal/HER2-low breast cancer: PILHLE-001 study.","authors":"Chang Gong, Yuan Xia, Yingying Zhu, Yaping Yang, Qun Lin, Qiang Liu, Wenqian Yang, Li Ling, Jiajie Zhong, Zhuxi Duan, Yunjie Zeng, Ziliang Cheng, Jun Shen, Yinduo Zeng, Louis Wing Cheong Chow, Erwei Song","doi":"10.1016/j.xcrm.2024.101807","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101807","url":null,"abstract":"<p><p>The prognosis of patients with luminal/human epidermal growth factor receptor 2 (HER2)-low early breast cancer (EBC) needs to be improved. This preclinical study and phase 2 trial (ChiCTR2100047233) aims to explore the efficacy and safety of pyrotinib (a pan-HER tyrosine kinase inhibitor) plus chemotherapy in this population. Our preclinical experiments indicate a synergistic anti-tumor effect of pyrotinib plus chemotherapy in luminal/HER2-low (immunochemistry [IHC] 2+/fluorescent in situ hybridization [FISH]-negative) breast cancer models. Furthermore, 48 women with luminal/HER2-low (IHC 2+/FISH-negative) high-risk EBC are enrolled to receive neoadjuvant pyrotinib plus chemotherapy (epirubicin-cyclophosphamide followed by docetaxel). Ultimately, 26 (54.2%; 95% confidence interval [CI] 39.2%-68.6%) patients achieve the primary endpoint (residual cancer burden [RCB] 0/I). Treatment-related adverse events of grade ≥3 occur in 21 (43.8%) patients, with the most prevalent being diarrhea (10 [20.8%]). In conclusion, neoadjuvant pyrotinib plus chemotherapy has encouraging efficacy and manageable toxicity in women with luminal/HER2-low (IHC 2+/FISH-negative) high-risk EBC. This regimen warrants to be further validated.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101807"},"PeriodicalIF":11.7,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142602901","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}
Tristan Tay, Gayathri Bommakanti, Elizabeth Jaensch, Aparna Gorthi, Iswarya Karapa Reddy, Yan Hu, Ruochi Zhang, Aatman S Doshi, Sin Lih Tan, Verena Brucklacher-Waldert, Laura Prickett, James Kurasawa, Michael Glen Overstreet, Steven Criscione, Jason Daniel Buenrostro, Deanna A Mele
{"title":"Degradation of IKZF1 prevents epigenetic progression of T cell exhaustion in an antigen-specific assay.","authors":"Tristan Tay, Gayathri Bommakanti, Elizabeth Jaensch, Aparna Gorthi, Iswarya Karapa Reddy, Yan Hu, Ruochi Zhang, Aatman S Doshi, Sin Lih Tan, Verena Brucklacher-Waldert, Laura Prickett, James Kurasawa, Michael Glen Overstreet, Steven Criscione, Jason Daniel Buenrostro, Deanna A Mele","doi":"10.1016/j.xcrm.2024.101804","DOIUrl":"https://doi.org/10.1016/j.xcrm.2024.101804","url":null,"abstract":"<p><p>In cancer, chronic antigen stimulation drives effector T cells to exhaustion, limiting the efficacy of T cell therapies. Recent studies have demonstrated that epigenetic rewiring governs the transition of T cells from effector to exhausted states and makes a subset of exhausted T cells non-responsive to PD1 checkpoint blockade. Here, we describe an antigen-specific assay for T cell exhaustion that generates T cells phenotypically and transcriptionally similar to those found in human tumors. We perform a screen of human epigenetic regulators, identifying IKZF1 as a driver of T cell exhaustion. We determine that the IKZF1 degrader iberdomide prevents exhaustion by blocking chromatin remodeling at T cell effector enhancers and preserving the binding of AP-1, NF-κB, and NFAT. Thus, our study uncovers a role for IKZF1 as a driver of T cell exhaustion through epigenetic modulation, providing a rationale for the use of iberdomide in solid tumors to prevent T cell exhaustion.</p>","PeriodicalId":9822,"journal":{"name":"Cell Reports Medicine","volume":" ","pages":"101804"},"PeriodicalIF":11.7,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142563644","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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