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The work identifies and characterizes the T cell receptor T104 for the KRAS.G12V mutation and shows selective recognition and potent killing of KRAS.G12V-expressing tumor cells. Lymphodepleting chemotherapy markedly augments tumor cell killing across multiple cancer models, driven by immunoproteasome activation and HLA-I upregulation, which remodels the immunopeptidome and enhances neoantigen availability.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/lymphodepleting-chemotherapy-potentiates-neoantigen-directed-t-cell-therapy-by-enhancing-antigen-presentation/434135/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/lymphodepleting-chemotherapy-potentiates-neoantigen-directed-t-cell-therapy-by-enhancing-antigen-presentation/434135.png","ImageObject",300,407,{"name":92,"@type":93},"Mia  ","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the main barrier to adoptive cell therapy effectiveness in solid tumors?","Question",{"text":113,"@type":114},"Limited neoantigen presentation, including insufficient antigen presentation machinery and restricted immunoproteasome activity, can reduce the availability of presented neoantigens for T cells.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which mutation-specific T cell receptor is characterized in this article?",{"text":118,"@type":114},"The article identifies and characterizes a KRAS.G12V-specific T cell receptor, T104, that selectively recognizes and kills KRAS.G12V-expressing tumor cells.",{"name":120,"@type":111,"acceptedAnswer":121},"How does lymphodepleting chemotherapy improve neoantigen-directed T cell therapy?",{"text":122,"@type":114},"It upregulates immunoproteasome activity and HLA-I surface expression, remodeling the antigenic landscape by increasing peptide abundance and changing immunopeptidome features to improve T cell-mediated tumor recognition.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},434135,1790823184,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},687207024478,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Article  \nLymphodepleting chemotherapy potentiates neoantigen-directed T cell therapy by enhancing antigen presentation  \nGraphical abstract  \nKRAS G12V specific TCR  \nGzmB  \n| \u003Cbr>Lymphodepleting chemotherapy\u003Cbr>Cy+Flu | \u003Cbr>\u003Cbr>HLA-I \u003Cbr>Immunoproteasome  Expanded antigenic landscape | T Cell\u003Cbr>\u003Cbr>\u003Cbr>Synergisitic T-cell killing |\n| --- | --- | --- |\n\nHighlights  \nAuthors  \nShira Sagie, Tomer Babu, Chen Weller, ..., Omer Dushek, Charlotte M. Deane, Yardena Samuels  \nCorrespondence  \n[yardena.samuels@weizmann.ac.il](yardena.samuels@weizmann.ac.il)  \nIn brief  \nSagie et al. identify a KRAS.G12V-specific TCR and show that lymphodepleting chemotherapy enhances antigen presentation via immunoproteasome activation and HLA-I upregulation. Together, these changes synergize to improve T cell-mediated tumor killing in multiple models and highlight the potential of optimized chemotherapy to augment adoptive cell therapy efficacy.  \n• Discovery of a KRAS.G12V-specific TCR with potent and specific tumor killing  \n• Lymphodepleting chemotherapy synergizes with ACT and T cell engagers across neoantigens  \n• Chemotherapy remodels the tumor antigenic landscape and enhances neoantigen presentation  \n• Chemotherapy increases immunoproteasome activity and HLA-I surface expression  \nSagie et al., 2025, Cell Reports Medicine 6, 102506  \nDecember 16, 2025 © 2025 The Author(s) . Published by Elsevier Inc.  \n[https://doi.org/10.1016/j.xcrm.2025.102506](https://doi.org/10.1016/j.xcrm.2025.102506)  \nll  \nll  \nOPEN ACCESS  \nArticle  \nLymphodepleting chemotherapy potentiates neoantigen-directed T cell therapy by enhancing antigen presentation  \nShira Sagie,1,2,14 Tomer Babu,1,14 Chen Weller,1 Claire Tabachnik,1 Ido Livneh,4,5 Nele P. Quast,3 Nofar Gumpert,1 Alina Shomuradova,6 Matthew I. Raybould,3 Ronen Levy,1 Dmitry Malko,1 Adi Alfia,7 Talal Ben Lulu,1 Michal Alon,1 Franco Herrera,1 Mikhail Kutuzov,6 Mirie Zerbib,8 Polina Greenberg,1 Talya Wasserman-Bartov,1 Gil Benedek,9  \nYishai Levin,10 Chani Stossel,2,11 Iris Kamer,2,11 Talia Golan,2,11 Roni Oren,8 Merav Shmueli,12 Osnat Bartok,1 Jair Bar,2,11 Jonathan Cohen,13 Omer Dushek,6 Charlotte M. Deane,3 and Yardena Samuels1,15,*  \n1Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel  \n2Jusidman Cancer Center, Sheba Medical Center, Ramat Gan 52621, Israel  \n3Department of Statistics, University of Oxford, OX1 3LB Oxford, UK  \n4Rappaport Technion Cancer Research center, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel  \n5Institute of Pathology, Rambam Health Care Campus, Haifa 3109601, Israel  \n6Sir William Dunn School of Pathology, University of Oxford, OX1 3RE Oxford, UK  \n7Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel  \n8Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 7610001, Israel  \n9Faculty of Medicine, Hadassah Hebrew-University Medical Center, Jerusalem 91120, Israel  \n10INCPM, Weizmann Institute of Science, Rehovot 7610001, Israel  \n11Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel  \n12Department of Systems Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel  \n13Sharett Institute of Oncology, Hadassah Cancer Research Institute and The Wohl Institute for Translational Medicine, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel  \n14These authors contributed equally  \n15Lead contact  \n*Correspondence: [yardena.samuels@weizmann.ac.il](yardena.samuels@weizmann.ac.il)[ ](yardena.samuels@weizmann.ac.il)[https://doi.org/10.1016/j.xcrm.2025.102506](https://doi.org/10.1016/j.xcrm.2025.102506)  \nSUMMARY  \nAdoptive cell therapy (ACT) targeting tumor-specific antigens holds promise for solid tumors, but limited neoantigen presentation remains a key barrier to efficacy. Here, we identify and characterize a T cell receptor (TCR), T104, for the KRAS.G12V mutation, a prevalent neoanti","cbCaiin1VEKPiWMe","https://ap.wps.com/l/cbCaiin1VEKPiWMe","pdf",6623944,31,"English","# Summary\n# Highlights\n# Summary\n# Introduction\n## Background on neoantigen presentation barriers\n## Adoptive cell therapy and KRAS.G12V targeting","[{\"question\":\"What is the main barrier to adoptive cell therapy effectiveness in solid tumors?\",\"answer\":\"Limited neoantigen presentation, including insufficient antigen presentation machinery and restricted immunoproteasome activity, can reduce the availability of presented neoantigens for T cells.\"},{\"question\":\"Which mutation-specific T cell receptor is characterized in this article?\",\"answer\":\"The article identifies and characterizes a KRAS.G12V-specific T cell receptor, T104, that selectively recognizes and kills KRAS.G12V-expressing tumor cells.\"},{\"question\":\"How does lymphodepleting chemotherapy improve neoantigen-directed T cell therapy?\",\"answer\":\"It upregulates immunoproteasome activity and HLA-I surface expression, remodeling the antigenic landscape by increasing peptide abundance and changing immunopeptidome features to improve T cell-mediated tumor recognition.\"}]","Lymphodepleting chemotherapy potentiates neoantigen-directed T cell therapy by enhancing antigen presentation | PDF",1790667198,78]