Expression of CD137 on Hodgkin and Reed―Sternberg Cells Inhibits T-cell Activation by Eliminating CD137 Ligand Expression
Hodgkin lymphoma is caused by a minority population of malignant Hodgkin and Reed-Sternberg (HRS) cells that recruit an abundance of inflammatory cells. The long-term survival of HRS cells among the vast majority of immune cells indicates that they have developed potent immune escape mechanisms. We...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2013-01, Vol.73 (2), p.652-661 |
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| creator | HO, Weng Tong WAN LU PANG SCHWARZ, Herbert CHONG, Siew Meng CASTELLA, Antonio AL-SALAM, Suhail TAN, Teng Ee MOH, Mei Chung KOH, Liang Kai GAN, Shu Uin CHENG, Cheong Kin |
| description | Hodgkin lymphoma is caused by a minority population of malignant Hodgkin and Reed-Sternberg (HRS) cells that recruit an abundance of inflammatory cells. The long-term survival of HRS cells among the vast majority of immune cells indicates that they have developed potent immune escape mechanisms. We report that the TNF receptor family member CD137 (TNFRSF9) is expressed on HRS cells, while normal B cells, from which HRS cells are most often derived, do not express CD137. In 48 of 53 cases of classical Hodgkin lymphoma, CD137 was detected on HRS cells. Ectopically expressed CD137 transferred by trogocytosis from HRS cells to neighboring HRS and antigen-presenting cells, which constitutively express the CD137 ligand (CD137L and TNFSF9), became associated with CD137L and the CD137-CD137L complex was internalized. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-γ release and proliferation. Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma. |
| doi_str_mv | 10.1158/0008-5472.CAN-12-3849 |
| format | Article |
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The long-term survival of HRS cells among the vast majority of immune cells indicates that they have developed potent immune escape mechanisms. We report that the TNF receptor family member CD137 (TNFRSF9) is expressed on HRS cells, while normal B cells, from which HRS cells are most often derived, do not express CD137. In 48 of 53 cases of classical Hodgkin lymphoma, CD137 was detected on HRS cells. Ectopically expressed CD137 transferred by trogocytosis from HRS cells to neighboring HRS and antigen-presenting cells, which constitutively express the CD137 ligand (CD137L and TNFSF9), became associated with CD137L and the CD137-CD137L complex was internalized. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-γ release and proliferation. Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-12-3849</identifier><identifier>PMID: 23204227</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>4-1BB Ligand - metabolism ; Antineoplastic agents ; Biological and medical sciences ; Cell Line, Tumor ; Hematologic and hematopoietic diseases ; Hodgkin Disease - immunology ; Humans ; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis ; Lymphocyte Activation - immunology ; Medical sciences ; Pharmacology. Drug treatments ; Reed-Sternberg Cells - immunology ; T-Lymphocytes - immunology ; Tumor Escape ; Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2013-01, Vol.73 (2), p.652-661</ispartof><rights>2014 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c386t-a5a3672ff58d92b502d2859b35daf94473df0e9f6a683344b8c9b57a1230f6dc3</citedby><cites>FETCH-LOGICAL-c386t-a5a3672ff58d92b502d2859b35daf94473df0e9f6a683344b8c9b57a1230f6dc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,3343,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=27062198$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23204227$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>HO, Weng Tong</creatorcontrib><creatorcontrib>WAN LU PANG</creatorcontrib><creatorcontrib>SCHWARZ, Herbert</creatorcontrib><creatorcontrib>CHONG, Siew Meng</creatorcontrib><creatorcontrib>CASTELLA, Antonio</creatorcontrib><creatorcontrib>AL-SALAM, Suhail</creatorcontrib><creatorcontrib>TAN, Teng Ee</creatorcontrib><creatorcontrib>MOH, Mei Chung</creatorcontrib><creatorcontrib>KOH, Liang Kai</creatorcontrib><creatorcontrib>GAN, Shu Uin</creatorcontrib><creatorcontrib>CHENG, Cheong Kin</creatorcontrib><title>Expression of CD137 on Hodgkin and Reed―Sternberg Cells Inhibits T-cell Activation by Eliminating CD137 Ligand Expression</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Hodgkin lymphoma is caused by a minority population of malignant Hodgkin and Reed-Sternberg (HRS) cells that recruit an abundance of inflammatory cells. The long-term survival of HRS cells among the vast majority of immune cells indicates that they have developed potent immune escape mechanisms. We report that the TNF receptor family member CD137 (TNFRSF9) is expressed on HRS cells, while normal B cells, from which HRS cells are most often derived, do not express CD137. In 48 of 53 cases of classical Hodgkin lymphoma, CD137 was detected on HRS cells. Ectopically expressed CD137 transferred by trogocytosis from HRS cells to neighboring HRS and antigen-presenting cells, which constitutively express the CD137 ligand (CD137L and TNFSF9), became associated with CD137L and the CD137-CD137L complex was internalized. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-γ release and proliferation. Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma.</description><subject>4-1BB Ligand - metabolism</subject><subject>Antineoplastic agents</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Hodgkin Disease - immunology</subject><subject>Humans</subject><subject>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</subject><subject>Lymphocyte Activation - immunology</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Reed-Sternberg Cells - immunology</subject><subject>T-Lymphocytes - immunology</subject><subject>Tumor Escape</subject><subject>Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkM1OGzEURq2qqKQpj9DKm0psBvw79iyjIYVIEUgU1pZnbKcuE0-wJwjUDS_RF-RJ8CgBVva1zvdd6wDwHaMTjLk8RQjJgjNBTurZZYFJQSWrPoEJ5lQWgjH-GUzemUPwNaW_eeQY8S_gkFCCGCFiAv7NHzfRpuT7AHsH6zNMBcz3i96s7nyAOhh4ba15ef7_e7AxNDauYG27LsFF-OMbPyR4U7T5Ac7awT_oYWxqnuC882sf8hhW-9alX41tHwu_gQOnu2SP9ucU3P6a39QXxfLqfFHPlkVLZTkUmmtaCuIcl6YiDUfEEMmrhnKjXcWYoMYhW7lSl5JSxhrZVg0XGhOKXGlaOgXHu95N7O-3Ng1q7dP4ZR1sv00KE0FLLkVOTwHfoW3sU4rWqU30ax2fFEZq9K5Gp2p0qrL3HFWj95z7sV-xbdbWvKfeRGfg5x7QqdWdizq0Pn1wApUEV5K-ApU3iwc</recordid><startdate>20130115</startdate><enddate>20130115</enddate><creator>HO, Weng Tong</creator><creator>WAN LU PANG</creator><creator>SCHWARZ, Herbert</creator><creator>CHONG, Siew Meng</creator><creator>CASTELLA, Antonio</creator><creator>AL-SALAM, Suhail</creator><creator>TAN, Teng Ee</creator><creator>MOH, Mei Chung</creator><creator>KOH, Liang Kai</creator><creator>GAN, Shu Uin</creator><creator>CHENG, Cheong Kin</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><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></search><sort><creationdate>20130115</creationdate><title>Expression of CD137 on Hodgkin and Reed―Sternberg Cells Inhibits T-cell Activation by Eliminating CD137 Ligand Expression</title><author>HO, Weng Tong ; WAN LU PANG ; SCHWARZ, Herbert ; CHONG, Siew Meng ; CASTELLA, Antonio ; AL-SALAM, Suhail ; TAN, Teng Ee ; MOH, Mei Chung ; KOH, Liang Kai ; GAN, Shu Uin ; CHENG, Cheong Kin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c386t-a5a3672ff58d92b502d2859b35daf94473df0e9f6a683344b8c9b57a1230f6dc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>4-1BB Ligand - metabolism</topic><topic>Antineoplastic agents</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Hodgkin Disease - immunology</topic><topic>Humans</topic><topic>Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis</topic><topic>Lymphocyte Activation - immunology</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Reed-Sternberg Cells - immunology</topic><topic>T-Lymphocytes - immunology</topic><topic>Tumor Escape</topic><topic>Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>HO, Weng Tong</creatorcontrib><creatorcontrib>WAN LU PANG</creatorcontrib><creatorcontrib>SCHWARZ, Herbert</creatorcontrib><creatorcontrib>CHONG, Siew Meng</creatorcontrib><creatorcontrib>CASTELLA, Antonio</creatorcontrib><creatorcontrib>AL-SALAM, Suhail</creatorcontrib><creatorcontrib>TAN, Teng Ee</creatorcontrib><creatorcontrib>MOH, Mei Chung</creatorcontrib><creatorcontrib>KOH, Liang Kai</creatorcontrib><creatorcontrib>GAN, Shu Uin</creatorcontrib><creatorcontrib>CHENG, Cheong Kin</creatorcontrib><collection>Pascal-Francis</collection><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><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>HO, Weng Tong</au><au>WAN LU PANG</au><au>SCHWARZ, Herbert</au><au>CHONG, Siew Meng</au><au>CASTELLA, Antonio</au><au>AL-SALAM, Suhail</au><au>TAN, Teng Ee</au><au>MOH, Mei Chung</au><au>KOH, Liang Kai</au><au>GAN, Shu Uin</au><au>CHENG, Cheong Kin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Expression of CD137 on Hodgkin and Reed―Sternberg Cells Inhibits T-cell Activation by Eliminating CD137 Ligand Expression</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2013-01-15</date><risdate>2013</risdate><volume>73</volume><issue>2</issue><spage>652</spage><epage>661</epage><pages>652-661</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><abstract>Hodgkin lymphoma is caused by a minority population of malignant Hodgkin and Reed-Sternberg (HRS) cells that recruit an abundance of inflammatory cells. The long-term survival of HRS cells among the vast majority of immune cells indicates that they have developed potent immune escape mechanisms. We report that the TNF receptor family member CD137 (TNFRSF9) is expressed on HRS cells, while normal B cells, from which HRS cells are most often derived, do not express CD137. In 48 of 53 cases of classical Hodgkin lymphoma, CD137 was detected on HRS cells. Ectopically expressed CD137 transferred by trogocytosis from HRS cells to neighboring HRS and antigen-presenting cells, which constitutively express the CD137 ligand (CD137L and TNFSF9), became associated with CD137L and the CD137-CD137L complex was internalized. Disappearance of CD137L from the surface of HRS and antigen-presenting cells led to reduced costimulation of T cells through CD137, reducing IFN-γ release and proliferation. Our results reveal a new regulatory mechanism for CD137L expression that mediates immune escape by HRS cells, and they identify CD137 as a candidate target for immunotherapy of Hodgkin lymphoma.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>23204227</pmid><doi>10.1158/0008-5472.CAN-12-3849</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 4-1BB Ligand - metabolism Antineoplastic agents Biological and medical sciences Cell Line, Tumor Hematologic and hematopoietic diseases Hodgkin Disease - immunology Humans Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis Lymphocyte Activation - immunology Medical sciences Pharmacology. Drug treatments Reed-Sternberg Cells - immunology T-Lymphocytes - immunology Tumor Escape Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism Tumors |
| title | Expression of CD137 on Hodgkin and Reed―Sternberg Cells Inhibits T-cell Activation by Eliminating CD137 Ligand Expression |
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