Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells
The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8 T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered...
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| Veröffentlicht in: | Cancer immunology research 2016-11, Vol.4 (11), p.936-947 |
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| creator | Brea, Elliott J Oh, Claire Y Manchado, Eusebio Budhu, Sadna Gejman, Ron S Mo, George Mondello, Patrizia Han, James E Jarvis, Casey A Ulmert, David Xiang, Qing Chang, Aaron Y Garippa, Ralph J Merghoub, Taha Wolchok, Jedd D Rosen, Neal Lowe, Scott W Scheinberg, David A |
| description | The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8
T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. Cancer Immunol Res; 4(11); 936-47. ©2016 AACR. |
| doi_str_mv | 10.1158/2326-6066.cir-16-0177 |
| format | Article |
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T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. Cancer Immunol Res; 4(11); 936-47. ©2016 AACR.</description><identifier>ISSN: 2326-6066</identifier><identifier>EISSN: 2326-6074</identifier><identifier>DOI: 10.1158/2326-6066.cir-16-0177</identifier><identifier>PMID: 27680026</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; B7-H1 Antigen - metabolism ; CD8-Positive T-Lymphocytes - immunology ; CD8-Positive T-Lymphocytes - metabolism ; Cell Line, Tumor ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic ; Histocompatibility Antigens Class I - genetics ; Histocompatibility Antigens Class I - immunology ; Histocompatibility Antigens Class I - metabolism ; HLA-A Antigens - genetics ; HLA-A Antigens - immunology ; HLA-A Antigens - metabolism ; Humans ; Immunotherapy ; MAP Kinase Signaling System ; Melanoma, Experimental ; Mice ; Mice, Transgenic ; Neoplasms - genetics ; Neoplasms - immunology ; Neoplasms - metabolism ; Phosphotransferases - metabolism ; Programmed Cell Death 1 Receptor - metabolism ; RNA Interference ; RNA, Small Interfering - genetics</subject><ispartof>Cancer immunology research, 2016-11, Vol.4 (11), p.936-947</ispartof><rights>2016 American Association for Cancer Research.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c529t-3439be8831b8a0450638efe1155cc9ab4d50eca28233f310c09e3b15bdabe1a13</citedby><cites>FETCH-LOGICAL-c529t-3439be8831b8a0450638efe1155cc9ab4d50eca28233f310c09e3b15bdabe1a13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3342,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27680026$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brea, Elliott J</creatorcontrib><creatorcontrib>Oh, Claire Y</creatorcontrib><creatorcontrib>Manchado, Eusebio</creatorcontrib><creatorcontrib>Budhu, Sadna</creatorcontrib><creatorcontrib>Gejman, Ron S</creatorcontrib><creatorcontrib>Mo, George</creatorcontrib><creatorcontrib>Mondello, Patrizia</creatorcontrib><creatorcontrib>Han, James E</creatorcontrib><creatorcontrib>Jarvis, Casey A</creatorcontrib><creatorcontrib>Ulmert, David</creatorcontrib><creatorcontrib>Xiang, Qing</creatorcontrib><creatorcontrib>Chang, Aaron Y</creatorcontrib><creatorcontrib>Garippa, Ralph J</creatorcontrib><creatorcontrib>Merghoub, Taha</creatorcontrib><creatorcontrib>Wolchok, Jedd D</creatorcontrib><creatorcontrib>Rosen, Neal</creatorcontrib><creatorcontrib>Lowe, Scott W</creatorcontrib><creatorcontrib>Scheinberg, David A</creatorcontrib><title>Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells</title><title>Cancer immunology research</title><addtitle>Cancer Immunol Res</addtitle><description>The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8
T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. Cancer Immunol Res; 4(11); 936-47. ©2016 AACR.</description><subject>Animals</subject><subject>B7-H1 Antigen - metabolism</subject><subject>CD8-Positive T-Lymphocytes - immunology</subject><subject>CD8-Positive T-Lymphocytes - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Disease Models, Animal</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Histocompatibility Antigens Class I - genetics</subject><subject>Histocompatibility Antigens Class I - immunology</subject><subject>Histocompatibility Antigens Class I - metabolism</subject><subject>HLA-A Antigens - genetics</subject><subject>HLA-A Antigens - immunology</subject><subject>HLA-A Antigens - metabolism</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>MAP Kinase Signaling System</subject><subject>Melanoma, Experimental</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Neoplasms - genetics</subject><subject>Neoplasms - immunology</subject><subject>Neoplasms - metabolism</subject><subject>Phosphotransferases - metabolism</subject><subject>Programmed Cell Death 1 Receptor - metabolism</subject><subject>RNA Interference</subject><subject>RNA, Small Interfering - genetics</subject><issn>2326-6066</issn><issn>2326-6074</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUcFOwzAMjRCIobFPAOXIpSNOmiy9IKFqsMEmpAnOUZq5o6hrR7Ii-HtaNibwxZb9_Gw_E3IBbAgg9TUXXEWKKTV0hY9ARQxGoyNyts-P4uNDrFSPDEJ4Y61pHYOMT0mPj5RmjKsz8vBYVDYgXeCqKe22qCta53TSrG1F55OUpqUNgU7pvC7RNSXS8efGYwg_wIqmtnLoaYplGc7JSW7LgIO975OXu_FzOolmT_fT9HYWOcmTbSRikWSotYBMWxZLpoTGHNu7pHOJzeKlZOgs11yIXABzLEGRgcyWNkOwIPrkZse7abI1Lh1WW29Ls_HF2vovU9vC_K9UxatZ1R9GAjAOrCW42hP4-r3BsDXrIrj2BFth3QQDWkjJ40TJFip3UOfrEDzmhzHATPcK08lsOplNOl0YUKZ7Rdt3-XfHQ9ev8OIbj86Enw</recordid><startdate>20161101</startdate><enddate>20161101</enddate><creator>Brea, Elliott J</creator><creator>Oh, Claire Y</creator><creator>Manchado, Eusebio</creator><creator>Budhu, Sadna</creator><creator>Gejman, Ron S</creator><creator>Mo, George</creator><creator>Mondello, Patrizia</creator><creator>Han, James E</creator><creator>Jarvis, Casey A</creator><creator>Ulmert, David</creator><creator>Xiang, Qing</creator><creator>Chang, Aaron Y</creator><creator>Garippa, Ralph J</creator><creator>Merghoub, Taha</creator><creator>Wolchok, Jedd D</creator><creator>Rosen, Neal</creator><creator>Lowe, Scott W</creator><creator>Scheinberg, David A</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>20161101</creationdate><title>Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells</title><author>Brea, Elliott J ; Oh, Claire Y ; Manchado, Eusebio ; Budhu, Sadna ; Gejman, Ron S ; Mo, George ; Mondello, Patrizia ; Han, James E ; Jarvis, Casey A ; Ulmert, David ; Xiang, Qing ; Chang, Aaron Y ; Garippa, Ralph J ; Merghoub, Taha ; Wolchok, Jedd D ; Rosen, Neal ; Lowe, Scott W ; Scheinberg, David A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c529t-3439be8831b8a0450638efe1155cc9ab4d50eca28233f310c09e3b15bdabe1a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Animals</topic><topic>B7-H1 Antigen - metabolism</topic><topic>CD8-Positive T-Lymphocytes - immunology</topic><topic>CD8-Positive T-Lymphocytes - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Disease Models, Animal</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Histocompatibility Antigens Class I - genetics</topic><topic>Histocompatibility Antigens Class I - immunology</topic><topic>Histocompatibility Antigens Class I - metabolism</topic><topic>HLA-A Antigens - genetics</topic><topic>HLA-A Antigens - immunology</topic><topic>HLA-A Antigens - metabolism</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>MAP Kinase Signaling System</topic><topic>Melanoma, Experimental</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Neoplasms - genetics</topic><topic>Neoplasms - immunology</topic><topic>Neoplasms - metabolism</topic><topic>Phosphotransferases - metabolism</topic><topic>Programmed Cell Death 1 Receptor - metabolism</topic><topic>RNA Interference</topic><topic>RNA, Small Interfering - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brea, Elliott J</creatorcontrib><creatorcontrib>Oh, Claire Y</creatorcontrib><creatorcontrib>Manchado, Eusebio</creatorcontrib><creatorcontrib>Budhu, Sadna</creatorcontrib><creatorcontrib>Gejman, Ron S</creatorcontrib><creatorcontrib>Mo, George</creatorcontrib><creatorcontrib>Mondello, Patrizia</creatorcontrib><creatorcontrib>Han, James E</creatorcontrib><creatorcontrib>Jarvis, Casey A</creatorcontrib><creatorcontrib>Ulmert, David</creatorcontrib><creatorcontrib>Xiang, Qing</creatorcontrib><creatorcontrib>Chang, Aaron Y</creatorcontrib><creatorcontrib>Garippa, Ralph J</creatorcontrib><creatorcontrib>Merghoub, Taha</creatorcontrib><creatorcontrib>Wolchok, Jedd D</creatorcontrib><creatorcontrib>Rosen, Neal</creatorcontrib><creatorcontrib>Lowe, Scott W</creatorcontrib><creatorcontrib>Scheinberg, David A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer immunology research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brea, Elliott J</au><au>Oh, Claire Y</au><au>Manchado, Eusebio</au><au>Budhu, Sadna</au><au>Gejman, Ron S</au><au>Mo, George</au><au>Mondello, Patrizia</au><au>Han, James E</au><au>Jarvis, Casey A</au><au>Ulmert, David</au><au>Xiang, Qing</au><au>Chang, Aaron Y</au><au>Garippa, Ralph J</au><au>Merghoub, Taha</au><au>Wolchok, Jedd D</au><au>Rosen, Neal</au><au>Lowe, Scott W</au><au>Scheinberg, David A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells</atitle><jtitle>Cancer immunology research</jtitle><addtitle>Cancer Immunol Res</addtitle><date>2016-11-01</date><risdate>2016</risdate><volume>4</volume><issue>11</issue><spage>936</spage><epage>947</epage><pages>936-947</pages><issn>2326-6066</issn><eissn>2326-6074</eissn><abstract>The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8
T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference-based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output-dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. Cancer Immunol Res; 4(11); 936-47. ©2016 AACR.</abstract><cop>United States</cop><pmid>27680026</pmid><doi>10.1158/2326-6066.cir-16-0177</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer immunology research, 2016-11, Vol.4 (11), p.936-947 |
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| source | MEDLINE; American Association for Cancer Research; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals B7-H1 Antigen - metabolism CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - metabolism Cell Line, Tumor Disease Models, Animal Gene Expression Regulation, Neoplastic Histocompatibility Antigens Class I - genetics Histocompatibility Antigens Class I - immunology Histocompatibility Antigens Class I - metabolism HLA-A Antigens - genetics HLA-A Antigens - immunology HLA-A Antigens - metabolism Humans Immunotherapy MAP Kinase Signaling System Melanoma, Experimental Mice Mice, Transgenic Neoplasms - genetics Neoplasms - immunology Neoplasms - metabolism Phosphotransferases - metabolism Programmed Cell Death 1 Receptor - metabolism RNA Interference RNA, Small Interfering - genetics |
| title | Kinase Regulation of Human MHC Class I Molecule Expression on Cancer Cells |
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