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To find alternative immunomodulatory drugs that enhance chemotherapy, the study analyzes gene expression from cyclophosphamide responders versus non-responders and tests drug combinations across multiple murine cancer models. Tretinoin pretreatment is predicted to drive an interferon-associated tumor microenvironment, increasing CD8+ T-cell infiltration and sensitizing tumors to chemotherapy. Survival and cure benefits depend on CD4+ and CD8+ T cells, but the effect is model-selective and not reproduced in other cell lines, limiting clinical translation despite promising single-model data.",{"@graph":69,"@context":126},[70,84,105],{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/tretinoin-improves-the-anti-cancer-response-to-cyclophosphamide-in-a-model-selective-manner/330104/",{"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/tretinoin-improves-the-anti-cancer-response-to-cyclophosphamide-in-a-model-selective-manner/330104.png","ImageObject",300,407,{"name":92,"@type":93},"Himbo","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":24},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118,122],{"name":109,"@type":110,"acceptedAnswer":111},"Why is immune checkpoint therapy not effective for all patients?","Question",{"text":112,"@type":113},"Most patients do not respond to immune checkpoint therapy, and it can also cause severe side effects, including hyperprogressive disease.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What approach did the study use to identify candidate drugs?",{"text":117,"@type":113},"The researchers used gene expression data comparing cyclophosphamide responders and non-responders to identify existing clinically approved drugs that could mimic a chemosensitive tumor microenvironment, then tested combinations in multiple murine cancer models.",{"name":119,"@type":110,"acceptedAnswer":120},"How does tretinoin affect the tumor microenvironment and chemotherapy response?",{"text":121,"@type":113},"Tretinoin pretreatment induces an inflammatory, interferon-associated TME, increases infiltration of CD8+ T cells, and sensitizes tumors to subsequent cyclophosphamide chemotherapy.",{"name":123,"@type":110,"acceptedAnswer":124},"Why is the tretinoin plus cyclophosphamide strategy deprioritized for clinical translation?",{"text":125,"@type":113},"Although it improved survival and cure in a CD4+ and CD8+ T cell dependent manner in one model, the benefit was model-selective and could not be replicated using other cell lines or additional cancer models.","https://schema.org",{"og:url":83,"og:type":128,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":130,"canonical":83},"index,follow",{"doc_id":132,"site_id":62},330104,1790164435,{"code":4,"msg":5,"data":135},{"doc_id":132,"user_id":136,"nickname":92,"user_avatar":137,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":138,"file_id":139,"file_url":140,"file_type":141,"file_size":142,"view_count":24,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":143,"language":144,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":145,"faqs":146,"seo_title":147,"seo_description":67,"update_tm":148,"read_time":149,"preview_page_count":4},687197100911,"https://ap-avatar.wpscdn.com/avatar/a000239b6f1da00475?x-image-process=image/resize,m_fixed,w_180,h_180&k=1785132997149421697","Tilsed etal. BMC Cancer (2024) 24:203 BMC Cancer  \n[https://doi.org/10.1186/s12885-024-11915-5](https://doi.org/10.1186/s12885-024-11915-5)  \nRESEARCH Open Access  \nTretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner  \nCaitlin M. Tilsed 1,2,3, M. Lizeth Orozco Morales4, Rachael M. Zemek4, Brianna A. Gordon5, Matthew J. Piggott5, Anna K. Nowak 1,2,3,6, Scott A. Fisher 1,2,3, Richard A. Lake 1,2,3 and W. Joost Lesterhuis 1,2,3,4*  \nAbstract  \nBackground Chemotherapy is included in treatment regimens for many solid cancers, but when administered asa single agent it is rarely curative. The addition of immune checkpoint therapy to standard chemotherapy regimens has improved response rates and increased survival in some cancers. However, most patients do not respond to treatment and immune checkpoint therapy can cause severe side effects. Therefore, there is a need for alternative immunomodulatory drugs that enhance chemotherapy.  \nMethods We used gene expression data from cyclophosphamide (CY) responders and non-responders to identify existing clinically approved drugs that could phenocopy a chemosensitive tumor microenvironment (TME), and tested combination treatments in multiple murine cancer models.  \nResults The vitamin A derivative tretinoin was the top predicted upstream regulator of response to CY. Tretinoin pretreatment induced an inflammatory, interferon-associated TME, with increased infiltration of CD8 + T cells, sensitizing the tumor to subsequent chemotherapy. However, while combination treatment significantly improved survival and cure rate in a CD4+ and CD8+ T cell dependent manner in AB1-HA murine mesothelioma, this effect was modelselective, and could not be replicated using other cell lines.  \nConclusions Despite the promising data in one model, the inability to validate the efficacy of combination treatment in multiple cancer models deprioritizes tretinoin/cyclophosphamide combination therapy for clinical translation.  \nKeywords Cyclophosphamide, Tretinoin, Interferon, Sensitisation, Combination treatment  \n*Correspondence:  \nW. Joost Lesterhuis [willem.lesterhuis@uwa.edu.au](willem.lesterhuis@uwa.edu.au)  \n1National Centre for Asbestos Related Diseases, 6009 Nedlands, WA, Australia  \n2School of Biomedical Sciences, University of Western Australia, 6009 Crawley, WA, Australia  \n3Institute for Respiratory Health, 6101 Perth, WA, Australia  \n4Telethon Kids Institute, University of Western Australia, 6872 West Perth, WA, Australia  \n5School of Molecular Sciences, University of Western Australia,  \n6009 Crawley, WA, Australia  \n6Department of Medical Oncology, Sir Charles Gairdner Hospital, 6009 Nedlands, WA, Australia  \n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/l](http://creativecommons.org/l)icenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ([http://creativecommons.org/publicdomain/zero/1.0/](http://creativecommons.org/publicdomain/zero/1.0/)) applies to the data made available in this article, unless otherwise stated in a credit line to the data.  \nTilsed et al. BMC Cancer (2024) 24:203  \nBackground  \nAlthough chemotherapy is used to treat many advanced or","cbCaiiorpwcDE2t8","https://ap.wps.com/l/cbCaiiorpwcDE2t8","pdf",4331508,11,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusions\n# Main text background and rationale\n## Chemotherapy and immune checkpoint therapy limitations\n## Need for alternative immunomodulatory drugs","[{\"question\":\"Why is immune checkpoint therapy not effective for all patients?\",\"answer\":\"Most patients do not respond to immune checkpoint therapy, and it can also cause severe side effects, including hyperprogressive disease.\"},{\"question\":\"What approach did the study use to identify candidate drugs?\",\"answer\":\"The researchers used gene expression data comparing cyclophosphamide responders and non-responders to identify existing clinically approved drugs that could mimic a chemosensitive tumor microenvironment, then tested combinations in multiple murine cancer models.\"},{\"question\":\"How does tretinoin affect the tumor microenvironment and chemotherapy response?\",\"answer\":\"Tretinoin pretreatment induces an inflammatory, interferon-associated TME, increases infiltration of CD8+ T cells, and sensitizes tumors to subsequent cyclophosphamide chemotherapy.\"},{\"question\":\"Why is the tretinoin plus cyclophosphamide strategy deprioritized for clinical translation?\",\"answer\":\"Although it improved survival and cure in a CD4+ and CD8+ T cell dependent manner in one model, the benefit was model-selective and could not be replicated using other cell lines or additional cancer models.\"}]","Tretinoin improves the anti-cancer response to cyclophosphamide, in a model-selective manner | PDF",1789987194,28]