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MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia
Deregulation of signaling pathways is a hallmark of malignant transformation. Signaling-associated phosphoproteins can be degraded to generate cancer-specific phosphopeptides that are presented by major histocompatibility complex (MHC) class I and II molecules and recognized by T cells; however, the...
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Published in: | Science translational medicine 2013-09, Vol.5 (203), p.203ra125-203ra125 |
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creator | Cobbold, Mark De La Peña, Hugo Norris, Andrew Polefrone, Joy M Qian, Jie English, Ann Michelle Cummings, Kara L Penny, Sarah Turner, James E Cottine, Jennifer Abelin, Jennifer G Malaker, Stacy A Zarling, Angela L Huang, Hsing-Wen Goodyear, Oliver Freeman, Sylvie D Shabanowitz, Jeffrey Pratt, Guy Craddock, Charles Williams, Michael E Hunt, Donald F Engelhard, Victor H |
description | Deregulation of signaling pathways is a hallmark of malignant transformation. Signaling-associated phosphoproteins can be degraded to generate cancer-specific phosphopeptides that are presented by major histocompatibility complex (MHC) class I and II molecules and recognized by T cells; however, the contribution of these phosphoprotein-specific T cells to immune surveillance is unclear. We identified 95 phosphopeptides presented on the surface of primary hematological tumors and normal tissues, including 61 that were tumor-specific. Phosphopeptides were more prevalent on more aggressive and malignant samples. CD8(+) T cell lines specific for these phosphopeptides recognized and killed both leukemia cell lines and human leukocyte antigen-matched primary leukemia cells ex vivo. Notably, healthy individuals showed robust CD8(+) T cell responses against many of these phosphopeptides within the circulating memory compartment. This immunity was significantly reduced or absent in some leukemia patients. This reduction correlated with clinical outcome; however, immunity was restored after allogeneic stem cell transplantation. These results suggest that phosphopeptides may be targets of cancer immune surveillance in humans, and point to their importance for development of vaccine-based and T cell adoptive transfer immunotherapies. |
doi_str_mv | 10.1126/scitranslmed.3006061 |
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Signaling-associated phosphoproteins can be degraded to generate cancer-specific phosphopeptides that are presented by major histocompatibility complex (MHC) class I and II molecules and recognized by T cells; however, the contribution of these phosphoprotein-specific T cells to immune surveillance is unclear. We identified 95 phosphopeptides presented on the surface of primary hematological tumors and normal tissues, including 61 that were tumor-specific. Phosphopeptides were more prevalent on more aggressive and malignant samples. CD8(+) T cell lines specific for these phosphopeptides recognized and killed both leukemia cell lines and human leukocyte antigen-matched primary leukemia cells ex vivo. Notably, healthy individuals showed robust CD8(+) T cell responses against many of these phosphopeptides within the circulating memory compartment. This immunity was significantly reduced or absent in some leukemia patients. This reduction correlated with clinical outcome; however, immunity was restored after allogeneic stem cell transplantation. These results suggest that phosphopeptides may be targets of cancer immune surveillance in humans, and point to their importance for development of vaccine-based and T cell adoptive transfer immunotherapies.</description><identifier>ISSN: 1946-6234</identifier><identifier>EISSN: 1946-6242</identifier><identifier>DOI: 10.1126/scitranslmed.3006061</identifier><identifier>PMID: 24048523</identifier><language>eng</language><publisher>United States</publisher><subject>CD8-Positive T-Lymphocytes - immunology ; Cells, Cultured ; Humans ; Immunity - immunology ; Leukemia - immunology ; Major Histocompatibility Complex ; Phosphopeptides - immunology ; T-Lymphocytes - immunology</subject><ispartof>Science translational medicine, 2013-09, Vol.5 (203), p.203ra125-203ra125</ispartof><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-ce33f2d5b025d4d994ca2075a35c3d63abf8acb46390214c78fa19624a52426b3</citedby><cites>FETCH-LOGICAL-c474t-ce33f2d5b025d4d994ca2075a35c3d63abf8acb46390214c78fa19624a52426b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24048523$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Cobbold, Mark</creatorcontrib><creatorcontrib>De La Peña, Hugo</creatorcontrib><creatorcontrib>Norris, Andrew</creatorcontrib><creatorcontrib>Polefrone, Joy M</creatorcontrib><creatorcontrib>Qian, Jie</creatorcontrib><creatorcontrib>English, Ann Michelle</creatorcontrib><creatorcontrib>Cummings, Kara L</creatorcontrib><creatorcontrib>Penny, Sarah</creatorcontrib><creatorcontrib>Turner, James E</creatorcontrib><creatorcontrib>Cottine, Jennifer</creatorcontrib><creatorcontrib>Abelin, Jennifer G</creatorcontrib><creatorcontrib>Malaker, Stacy A</creatorcontrib><creatorcontrib>Zarling, Angela L</creatorcontrib><creatorcontrib>Huang, Hsing-Wen</creatorcontrib><creatorcontrib>Goodyear, Oliver</creatorcontrib><creatorcontrib>Freeman, Sylvie D</creatorcontrib><creatorcontrib>Shabanowitz, Jeffrey</creatorcontrib><creatorcontrib>Pratt, Guy</creatorcontrib><creatorcontrib>Craddock, Charles</creatorcontrib><creatorcontrib>Williams, Michael E</creatorcontrib><creatorcontrib>Hunt, Donald F</creatorcontrib><creatorcontrib>Engelhard, Victor H</creatorcontrib><title>MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia</title><title>Science translational medicine</title><addtitle>Sci Transl Med</addtitle><description>Deregulation of signaling pathways is a hallmark of malignant transformation. Signaling-associated phosphoproteins can be degraded to generate cancer-specific phosphopeptides that are presented by major histocompatibility complex (MHC) class I and II molecules and recognized by T cells; however, the contribution of these phosphoprotein-specific T cells to immune surveillance is unclear. We identified 95 phosphopeptides presented on the surface of primary hematological tumors and normal tissues, including 61 that were tumor-specific. Phosphopeptides were more prevalent on more aggressive and malignant samples. CD8(+) T cell lines specific for these phosphopeptides recognized and killed both leukemia cell lines and human leukocyte antigen-matched primary leukemia cells ex vivo. Notably, healthy individuals showed robust CD8(+) T cell responses against many of these phosphopeptides within the circulating memory compartment. This immunity was significantly reduced or absent in some leukemia patients. This reduction correlated with clinical outcome; however, immunity was restored after allogeneic stem cell transplantation. These results suggest that phosphopeptides may be targets of cancer immune surveillance in humans, and point to their importance for development of vaccine-based and T cell adoptive transfer immunotherapies.</description><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>Cells, Cultured</subject><subject>Humans</subject><subject>Immunity - immunology</subject><subject>Leukemia - immunology</subject><subject>Major Histocompatibility Complex</subject><subject>Phosphopeptides - immunology</subject><subject>T-Lymphocytes - immunology</subject><issn>1946-6234</issn><issn>1946-6242</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><recordid>eNpVUclOwzAQtRCIlsIfIOQjlxRvcZsLEqqAViriAhculuNMWtMkDnaC1L_HqKUqh1mkefNmeQhdUzKmlMm7YGzndROqGooxJ0QSSU_QkGZCJpIJdnrIuRigixA-I2bKU3mOBkwQMU0ZH6KPl_kMm0qHgBdJ9M5Y3UGB27UL0VpoO1tAwNoD7tbRtF9BF7ArcQ2189ukshvAtq77xnZbbBtcQb-B2upLdFbqKsDVPo7Q-9Pj22yeLF-fF7OHZWLERHSJAc5LVqQ5YWkhiiwTRjMySTVPDS8k13k51SYXkmeEUWEm01LTLF6o03ilzPkI3e942z6PvzDQxL9UqvW21n6rnLbqf6Wxa7Vy30qQCZWMRILbPYF3Xz2ETtU2GKgq3YDrg6KCx005TXmEih3UeBeCh_IwhhL1K4s6lkXtZYltN8crHpr-dOA_HvGOfw</recordid><startdate>20130918</startdate><enddate>20130918</enddate><creator>Cobbold, Mark</creator><creator>De La Peña, Hugo</creator><creator>Norris, Andrew</creator><creator>Polefrone, Joy M</creator><creator>Qian, Jie</creator><creator>English, Ann Michelle</creator><creator>Cummings, Kara L</creator><creator>Penny, Sarah</creator><creator>Turner, James E</creator><creator>Cottine, Jennifer</creator><creator>Abelin, Jennifer G</creator><creator>Malaker, Stacy A</creator><creator>Zarling, Angela L</creator><creator>Huang, Hsing-Wen</creator><creator>Goodyear, Oliver</creator><creator>Freeman, Sylvie D</creator><creator>Shabanowitz, Jeffrey</creator><creator>Pratt, Guy</creator><creator>Craddock, Charles</creator><creator>Williams, Michael E</creator><creator>Hunt, Donald F</creator><creator>Engelhard, Victor H</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20130918</creationdate><title>MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia</title><author>Cobbold, Mark ; 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Signaling-associated phosphoproteins can be degraded to generate cancer-specific phosphopeptides that are presented by major histocompatibility complex (MHC) class I and II molecules and recognized by T cells; however, the contribution of these phosphoprotein-specific T cells to immune surveillance is unclear. We identified 95 phosphopeptides presented on the surface of primary hematological tumors and normal tissues, including 61 that were tumor-specific. Phosphopeptides were more prevalent on more aggressive and malignant samples. CD8(+) T cell lines specific for these phosphopeptides recognized and killed both leukemia cell lines and human leukocyte antigen-matched primary leukemia cells ex vivo. Notably, healthy individuals showed robust CD8(+) T cell responses against many of these phosphopeptides within the circulating memory compartment. This immunity was significantly reduced or absent in some leukemia patients. This reduction correlated with clinical outcome; however, immunity was restored after allogeneic stem cell transplantation. These results suggest that phosphopeptides may be targets of cancer immune surveillance in humans, and point to their importance for development of vaccine-based and T cell adoptive transfer immunotherapies.</abstract><cop>United States</cop><pmid>24048523</pmid><doi>10.1126/scitranslmed.3006061</doi><oa>free_for_read</oa></addata></record> |
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source | Alma/SFX Local Collection |
subjects | CD8-Positive T-Lymphocytes - immunology Cells, Cultured Humans Immunity - immunology Leukemia - immunology Major Histocompatibility Complex Phosphopeptides - immunology T-Lymphocytes - immunology |
title | MHC class I-associated phosphopeptides are the targets of memory-like immunity in leukemia |
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