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Tissue microarrays of 246 primary breast tumors assessed immune markers by immunohistochemistry, and an immune-competent CRISPR deletion mouse model evaluated immune composition by flow cytometry. METABRIC expression data linked immune marker levels to survival in ING4-altered basal disease, showing an ING4-associated suppressive microenvironment and worse outcomes with low GZMB. Collectively, findings indicate immune evasion coupled to metastatic progression.",{"@graph":69,"@context":122},[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/tumor-immune-microenvironment-permissive-to-metastatic-progression-of-ing4-deficient-breast-cancer/332201/",{"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/tumor-immune-microenvironment-permissive-to-metastatic-progression-of-ing4-deficient-breast-cancer/332201.png","ImageObject",300,407,{"name":92,"@type":93},"Maeve","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":19},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"How was the tumor immune microenvironment assessed in ING4-deficient breast cancer?","Question",{"text":112,"@type":113},"The study evaluated immune markers in human tissue microarrays using immunohistochemical staining and analyzed immune populations in an immune-competent CRISPR-based mouse model using flow cytometry. METABRIC gene expression data were also analyzed for survival links to immune markers.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What immune differences were observed in mice with Ing4-deleted tumors?",{"text":117,"@type":113},"Ing4-deleted mammary tumors showed increased tumor-associated macrophages (Gr-1lo CD11b+ F4/80+) and decreased granzyme B–positive (GzmB+) CD4+ T cells, consistent with a suppressive and/or less tumoricidal immune microenvironment.",{"name":119,"@type":110,"acceptedAnswer":120},"Which gene expression findings connected immune status to patient survival?",{"text":121,"@type":113},"Low expression of GZMB was significantly associated with poor survival, as was ING4-low expression in the basal subtype. Patients with GZMB-low/ING4-low tumors had the worst survival outcomes.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},332201,1791258256,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":19,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145,"preview_page_count":4},5909877438554,"https://ap-avatar.wpscdn.com/avatar/5600025385ad2bf12a7?_k=1778553567797529272","PLOS ONE  \nOPEN ACCESS  \nCitation: Tsutsumi E, Macy AM, LoBello J, Hastings KT, Kim S (2024) Tumor immune microenvironment permissive to metastatic progression of ING4-deficient breast cancer. PLoSONE 19(7): e0304194 . [https://doi.org/10.1371/](https://doi.org/10.1371/)[ ](https://doi.org/10.1371/)[journal.pone.0304194](journal.pone.0304194)  \nEditor: Yash Gupta, Penn State Health Milton S Hershey Medical Center, UNITED STATES  \nReceived: May 6, 2024  \nAccepted: June 20, 2024  \nPublished: July 5, 2024  \nPeer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here:  \n[https://doi.org/10.1371/journal.pone.0304194](https://doi.org/10.1371/journal.pone.0304194)  \n[Copyright:](Copyright: This is an open access article)[ This is an open access article](Copyright: This is an open access article), [free](free) of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.  \nData Availability Statement: All relevant data are within the manuscript.  \nFunding: The work was supported by National Health Institute/National Cancer Institute R03  \nRESEARCH ARTICLE  \nTumor immune microenvironment permissive to metastatic progression of ING4-deficient breast cancer  \nEmily Tsutsumi1,2, Anne M. Macy3,4, Janine LoBello5¤, Karen T. Hastings3,4, Suwon Kim1,2 *  \n1 Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States of America, 2 Cancer and Cell Biology Division, Translational Genomic Research Institute, Phoenix, Arizona, United States of America, 3 Department of Dermatology, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, United States of America, 4 Phoenix Veterans Affairs Health Care System, Phoenix, Arizona, United States of America, 5 Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, United States of America  \n¤ Current address: Exact Sciences, Phoenix, Arizona, United States of America  \n* [suwon@arizona.edu](suwon@arizona.edu)  \nAbstract  \nDeficiencies in the ING4 tumor suppressor are associated with advanced stage tumors and poor patient survival in cancer. ING4 was shown to inhibit NF-kB in several cancers. As NFkB is a key mediator of immune response, the ING4/NF-kB axis is likely to manifest in tumor-immune modulation but has not been investigated. To characterize the tumor immune microenvironment associated with ING4-deficient tumors, three approaches were employed in this study: First, tissue microarrays composed of 246 primary breast tumors including 97 ING4-deficient tumors were evaluated for the presence of selective immune markers, CD68, CD4, CD8, and PD-1, using immunohistochemical staining. Second, an immune-competent mouse model of ING4-deficient breast cancer was devised utilizing CRISPR-mediated deletion of Ing4 in a Tp53 deletion-derived mammary tumor cell line; mammary tumors were evaluated for immune markers using flow cytometry. Lastly, the METABRIC gene expression dataset was evaluated for patient survival related to the immune markers associated with Ing4-deleted tumors. The results showed that CD68, CD4, CD8, or PD-1, was not significantly associated with ING4-deficient breast tumors, indicating no enrichment of macrophages, T cells, or exhausted T cell types. In mice, Ing4-deleted mammary tumors had a growth rate comparable to Ing4-intact tumors but showed increased tumor penetrance and metastasis. Immune marker analyses of Ing4-deleted tumors revealed a significant increase in tumor-associated macrophages (Gr-1loCD11b+ F4/80+) and a decrease in granzyme B-positive (GzmB+) CD4+ T cells, indicating a suppressive ","cbCaisvzmPphCHIs","https://ap.wps.com/l/cbCaisvzmPphCHIs","pdf",2083307,21,"English","# Abstract\n## Study overview and rationale\n## Methods: human tissue analysis, mouse model, and METABRIC dataset\n## Key results: immune marker changes and survival associations\n## Conclusions on immune evasion and metastasis","[{\"question\":\"How was the tumor immune microenvironment assessed in ING4-deficient breast cancer?\",\"answer\":\"The study evaluated immune markers in human tissue microarrays using immunohistochemical staining and analyzed immune populations in an immune-competent CRISPR-based mouse model using flow cytometry. METABRIC gene expression data were also analyzed for survival links to immune markers.\"},{\"question\":\"What immune differences were observed in mice with Ing4-deleted tumors?\",\"answer\":\"Ing4-deleted mammary tumors showed increased tumor-associated macrophages (Gr-1lo CD11b+ F4/80+) and decreased granzyme B–positive (GzmB+) CD4+ T cells, consistent with a suppressive and/or less tumoricidal immune microenvironment.\"},{\"question\":\"Which gene expression findings connected immune status to patient survival?\",\"answer\":\"Low expression of GZMB was significantly associated with poor survival, as was ING4-low expression in the basal subtype. Patients with GZMB-low/ING4-low tumors had the worst survival outcomes.\"}]","Tumor immune microenvironment permissive to metastatic progression of ING4-deficient breast cancer | PDF",1789997293,53]