[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-375553-105":59,"doc-detail-375553-en":131},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":124,"head_meta":126,"extra_data":128,"updated_unix":130},105,"en","cancers-dark-matter-lighting-the-abyss-unveils-universe-of-new-therapies","Cancer’s Dark Matter - Lighting the Abyss Unveils Universe of New Therapies","","Cancer’s Dark Matter describes how noncanonical peptides (NCP) presented by tumor HLA class I molecules may escape recognition by endogenous tumor-reactive T cells and yet become immunogenic after sensitization. The text reports that in vitro sensitization can generate T cells recognizing shared epitopes across diverse cancers and naturally presented NCP on patient-derived tumor models. Evidence is discussed for cross-cancer sharing, analytical decoding by LC/MS-MS, and why newly discovered immunogenicity matters for therapeutic anticancer strategies.",{"@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/cancers-dark-matter-lighting-the-abyss-unveils-universe-of-new-therapies/375553/",{"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/cancers-dark-matter-lighting-the-abyss-unveils-universe-of-new-therapies/375553.png","ImageObject",300,407,{"name":92,"@type":93},"Lucas Martin","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-24",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 does the study identify as “Cancer’s Dark Matter”?","Question",{"text":113,"@type":114},"It refers to noncanonical peptides presented by HLA class I on cancer cells that show limited recognition by endogenous tumor-reactive T cells. The discussion highlights that these peptides can be targeted by T cells once properly sensitized.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How do peripheral blood lymphocytes contribute to T-cell recognition?",{"text":118,"@type":114},"The text explains that peripheral blood lymphocytes can be sensitized in vitro to recognize HLA-bound noncanonical tumor ligands and then secrete IFN-γ or upregulate activation markers like 4-1BB.",{"name":120,"@type":111,"acceptedAnswer":121},"Why are these noncanonical targets only being discovered now?",{"text":122,"@type":114},"The passage links delayed discovery to the difficulty of cross-presentation: short-lived noncanonical proteins may not be efficiently captured and presented by professional antigen-presenting cells. It also notes that analytical and computational decoding methods are still evolving.","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},375553,1790742447,{"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":81,"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":39},8796095360427,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","Cancer’s Dark Matter: Lighting the Abyss Unveils Universe of New Therapies  \nBernard A. Fox1,2,3, Walter J. Urba1, Shawn M. Jensen1, David B. Page1, Brendan D. Curti1, Rachel E. Sanborn1, and Rom S. Leidner1  \n◥  \nThe authors of a recent study identified noncanonical peptides (NCP) presented by cancer cells’ HLA and observed lack of reactivity to these antigens by endogenous tumor-reactive T cells. In vitro sensitization generated NCP-reactive T cells  \nthat recognized epitopes shared by a majority of cancers tested, providing opportunities for novel therapies to shared antigens.  \nSee related article by Lozano-Rabella et al., p. 2250  \nIn this issue of Clinical Cancer Research, Lozano-Rabella and colleagues (1) identified noncanonical peptides (NCP) presented by the HLAclassI molecules ofhuman tumor cell lines and demonstrated that these peptides were immunogenic (1) . While other publications support these findings of HLA presentation of noncanonical, aberrantly translated peptides derived from upstream open reading frame (uORF), 50 UTRs, ncRNAs, endogenous retroelements (ERE), pseudogenes and out-of-frame transcripts, from tumor cells, there has been little evidence that these rapidly degraded NCPs, or Dark Matter, were targets of the endogenous anticancer immune response (2–5) .  \nThe authors’ explore this question by determining whether tumorreactive T cells from the peripheral blood or tumor-infiltrating lymphocytes (TIL) recognized this HLA-bound Dark Matter, which they characterized as noncanonical tumor ligands (nonC-TL) . While there was no evidence of an endogenous immune response to the NCPs, in some instances peripheral blood lymphocytes (PBL) in vitro sensitized (IVS) to the nonC-TL recognized nonC-TL pulsed onto antigenpresenting cells (APC) and secreted IFNg or upregulated 4–1BB (Fig. 1) . These sensitized T cells also recognized the NCP naturally presented bythe patient’s tumor cell line as well as other cancer cell lines that shared the same HLA restriction element but represented different tumor types. Upon transfection with the appropriate restricting HLA molecule that presented the specific nonC-TL, two of three nonC-TL– reactive T cell cultures recognized a majority ofthe20þ tumor cell lines tested. This included endometrial, ovarian, gastrointestinal, and melanoma cancer cell lines and provided evidence for this HLA-bound Dark Matter to be shared by a spectrum of different cancers.  \nThe inability of short-lived noncanonical proteins to be picked-up, processed and cross-presented by professional APCs has been  \n1Robert W. Franz Cancer Center, Earle A. Chiles Research Institute, Providence Cancer Institute, Providence Portland Medical Center, Portland, Oregon. 2Department of Molecular Microbiology and Immunology, and Knight Cancer Institute, Oregon Health and Science University, Portland, Oregon. 3UbiVac, Portland, Oregon.  \nCorresponding Author: Bernard A. Fox, Harder Family Chair for Cancer Research, 2N56 North Pavilion, Earle A. Chiles Research Institute, Providence Portland Medical Center, 4805 NE Glisan, Portland, OR 97214 . E-mail:  \n[Bernard.fox@providence.org](Bernard.fox@providence.org)[ ](Bernard.fox@providence.org)[Clin Cancer Res 2023](Clin Cancer Res 2023);[29:2173](29:2173)–[5](5)  \n[doi:](doi: 10.1158/1078-0432.CCR-23-0422)[ 10.1158/1078-0432.CCR-23-0422](doi: 10.1158/1078-0432.CCR-23-0422)  \nThis open access article is distributed under the Creative Commons AttributionNonCommercial-NoDerivatives 4 . 0 International (CC BY-NC-ND 4 . 0) license.  \n􀀂2023The Authors;Published by the American Association for Cancer Research  \ndescribed previously (4) . Most of the noncanonical proteins/peptides are short-lived proteins(SLiP)or defective ribosomal products(DRiP), not subject to thymic selection, typically degraded within 30 minutes, but efficiently captured by MHC class I and thereby widely expressed on the surface of tumor cells (Fig. 1; refs. 4, 6) . While the stability provided by MHC binding allow","cbCaiccIco4ir3UR","https://ap.wps.com/l/cbCaiccIco4ir3UR","pdf",1428766,"English","# Key findings of noncanonical peptides (NCP)\n## Immunogenicity after sensitization\n# Implications for endogenous anticancer immunity\n## Cross-presentation limitations and protein turnover\n## LC/MS-MS decoding approaches\n# Historical context and future therapy rationale","[{\"question\":\"What does the study identify as “Cancer’s Dark Matter”?\",\"answer\":\"It refers to noncanonical peptides presented by HLA class I on cancer cells that show limited recognition by endogenous tumor-reactive T cells. The discussion highlights that these peptides can be targeted by T cells once properly sensitized.\"},{\"question\":\"How do peripheral blood lymphocytes contribute to T-cell recognition?\",\"answer\":\"The text explains that peripheral blood lymphocytes can be sensitized in vitro to recognize HLA-bound noncanonical tumor ligands and then secrete IFN-γ or upregulate activation markers like 4-1BB.\"},{\"question\":\"Why are these noncanonical targets only being discovered now?\",\"answer\":\"The passage links delayed discovery to the difficulty of cross-presentation: short-lived noncanonical proteins may not be efficiently captured and presented by professional antigen-presenting cells. It also notes that analytical and computational decoding methods are still evolving.\"}]","Cancer’s Dark Matter - Lighting the Abyss Unveils Universe of New Therapies | PDF",1790215344]