Low GILT expression is associated with poor patient survival in diffuse large B-cell lymphoma
The MHC class II-restricted antigen processing pathway presents antigenic peptides acquired in the endocytic route for the activation of CD4+ T cells. Multiple cancers express MHC class II, which may influence the anti-tumor immune response and patient outcome. Low MHC class II expression is assoc...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2013-12-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | http://journal.frontiersin.org/Journal/10.3389/fimmu.2013.00425/full |
| _version_ | 1811227148133859328 |
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| author | Hannah ePhipps-Yonas Hannah ePhipps-Yonas Haiyan eCui Noemi eSebastiao Patrick S. Brunhoeber Ellen eHaddock Martin J. Deymier Wolfram eKlapper Lonnie eLybarger Lonnie eLybarger Denise eRoe Denise eRoe Karen Taraszka Hastings Karen Taraszka Hastings Karen Taraszka Hastings |
| author_facet | Hannah ePhipps-Yonas Hannah ePhipps-Yonas Haiyan eCui Noemi eSebastiao Patrick S. Brunhoeber Ellen eHaddock Martin J. Deymier Wolfram eKlapper Lonnie eLybarger Lonnie eLybarger Denise eRoe Denise eRoe Karen Taraszka Hastings Karen Taraszka Hastings Karen Taraszka Hastings |
| author_sort | Hannah ePhipps-Yonas |
| collection | DOAJ |
| description | The MHC class II-restricted antigen processing pathway presents antigenic peptides acquired in the endocytic route for the activation of CD4+ T cells. Multiple cancers express MHC class II, which may influence the anti-tumor immune response and patient outcome. Low MHC class II expression is associated with poor survival in diffuse large B-cell lymphoma (DLBCL), the most common form of aggressive non-Hodgkin lymphoma. Therefore, we investigated whether gamma-interferon-inducible lysosomal thiol reductase (GILT), an upstream component of the MHC class II-restricted antigen processing pathway that is not regulated by the transcription factor class II transactivator, may be important in DLBCL biology. GILT reduces protein disulfide bonds in the endocytic compartment, exposing additional epitopes for MHC class II binding and facilitating antigen presentation. In each of four independent gene expression profiling cohorts with a total of 585 DLBCL patients, low GILT expression was significantly associated with poor overall survival. In contrast, low expression of a classical MHC class II gene, HLA-DRA, was associated with poor survival in one of four cohorts. The association of low GILT expression with poor survival was independent of established clinical and molecular prognostic factors, the International Prognostic Index and the cell of origin classification, respectively. Immunohistochemical analysis of GILT expression in 96 DLBCL cases demonstrated variation in GILT protein expression within tumor cells which correlated strongly with GILT mRNA expression. These studies identify a novel association between GILT expression and clinical outcome in lymphoma. Our findings underscore the role of antigen processing in DLBCL and suggest that molecules targeting this pathway warrant investigation as potential therapeutics. |
| first_indexed | 2024-04-12T09:36:26Z |
| format | Article |
| id | doaj.art-221e6cf8ba7d4d9382227deb30343492 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T09:36:26Z |
| publishDate | 2013-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-221e6cf8ba7d4d9382227deb303434922022-12-22T03:38:12ZengFrontiers Media S.A.Frontiers in Immunology1664-32242013-12-01410.3389/fimmu.2013.0042565988Low GILT expression is associated with poor patient survival in diffuse large B-cell lymphomaHannah ePhipps-Yonas0Hannah ePhipps-Yonas1Haiyan eCui2Noemi eSebastiao3Patrick S. Brunhoeber4Ellen eHaddock5Martin J. Deymier6Wolfram eKlapper7Lonnie eLybarger8Lonnie eLybarger9Denise eRoe10Denise eRoe11Karen Taraszka Hastings12Karen Taraszka Hastings13Karen Taraszka Hastings14University of Arizona College of Medicine PhoenixUniversity of ArizonaUniversity of ArizonaVentana Medical SystemsVentana Medical SystemsUniversity of Arizona College of Medicine PhoenixUniversity of ArizonaUniversitätsklinikum Schleswig-HolsteinUniversity of ArizonaUniversity of ArizonaUniversity of ArizonaUniversity of Arizona Mel and Enid Zuckerman College of Public HealthUniversity of Arizona College of Medicine PhoenixUniversity of ArizonaUniversity of ArizonaThe MHC class II-restricted antigen processing pathway presents antigenic peptides acquired in the endocytic route for the activation of CD4+ T cells. Multiple cancers express MHC class II, which may influence the anti-tumor immune response and patient outcome. Low MHC class II expression is associated with poor survival in diffuse large B-cell lymphoma (DLBCL), the most common form of aggressive non-Hodgkin lymphoma. Therefore, we investigated whether gamma-interferon-inducible lysosomal thiol reductase (GILT), an upstream component of the MHC class II-restricted antigen processing pathway that is not regulated by the transcription factor class II transactivator, may be important in DLBCL biology. GILT reduces protein disulfide bonds in the endocytic compartment, exposing additional epitopes for MHC class II binding and facilitating antigen presentation. In each of four independent gene expression profiling cohorts with a total of 585 DLBCL patients, low GILT expression was significantly associated with poor overall survival. In contrast, low expression of a classical MHC class II gene, HLA-DRA, was associated with poor survival in one of four cohorts. The association of low GILT expression with poor survival was independent of established clinical and molecular prognostic factors, the International Prognostic Index and the cell of origin classification, respectively. Immunohistochemical analysis of GILT expression in 96 DLBCL cases demonstrated variation in GILT protein expression within tumor cells which correlated strongly with GILT mRNA expression. These studies identify a novel association between GILT expression and clinical outcome in lymphoma. Our findings underscore the role of antigen processing in DLBCL and suggest that molecules targeting this pathway warrant investigation as potential therapeutics.http://journal.frontiersin.org/Journal/10.3389/fimmu.2013.00425/fullantigen processing and presentationtumor immunologyGILTMHC class IIdiffuse large B cell lymphoma |
| spellingShingle | Hannah ePhipps-Yonas Hannah ePhipps-Yonas Haiyan eCui Noemi eSebastiao Patrick S. Brunhoeber Ellen eHaddock Martin J. Deymier Wolfram eKlapper Lonnie eLybarger Lonnie eLybarger Denise eRoe Denise eRoe Karen Taraszka Hastings Karen Taraszka Hastings Karen Taraszka Hastings Low GILT expression is associated with poor patient survival in diffuse large B-cell lymphoma Frontiers in Immunology antigen processing and presentation tumor immunology GILT MHC class II diffuse large B cell lymphoma |
| title | Low GILT expression is associated with poor patient survival in diffuse large B-cell lymphoma |
| title_full | Low GILT expression is associated with poor patient survival in diffuse large B-cell lymphoma |
| title_fullStr | Low GILT expression is associated with poor patient survival in diffuse large B-cell lymphoma |
| title_full_unstemmed | Low GILT expression is associated with poor patient survival in diffuse large B-cell lymphoma |
| title_short | Low GILT expression is associated with poor patient survival in diffuse large B-cell lymphoma |
| title_sort | low gilt expression is associated with poor patient survival in diffuse large b cell lymphoma |
| topic | antigen processing and presentation tumor immunology GILT MHC class II diffuse large B cell lymphoma |
| url | http://journal.frontiersin.org/Journal/10.3389/fimmu.2013.00425/full |
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