Cargando…
Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies
BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) harbors somatic hypermutation (SHM) in the immunoglobulin heavy chain and light chain variable region genes, IGHV and IGK/LV. Recent studies have revealed that IGV SHM creates neoantigens that activate T-cell responses against B-cell lymphoma. METHOD...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806565/ https://www.ncbi.nlm.nih.gov/pubmed/31640780 http://dx.doi.org/10.1186/s40425-019-0730-x |
_version_ | 1783461661720444928 |
---|---|
author | Xu-Monette, Zijun Y. Li, Jianyong Xia, Yi Crossley, Beryl Bremel, Robert D. Miao, Yi Xiao, Min Snyder, Thomas Manyam, Ganiraju C. Tan, Xiaohong Zhang, Hongwei Visco, Carlo Tzankov, Alexandar Dybkaer, Karen Bhagat, Govind Tam, Wayne You, Hua Hsi, Eric D. van Krieken, J. Han Huh, Jooryung Ponzoni, Maurilio Ferreri, Andrés J. M. Møller, Michael B. Piris, Miguel A. Winter, Jane N. Medeiros, Jeffrey T. Xu, Bing Li, Yong Kirsch, Ilan Young, Ken H. |
author_facet | Xu-Monette, Zijun Y. Li, Jianyong Xia, Yi Crossley, Beryl Bremel, Robert D. Miao, Yi Xiao, Min Snyder, Thomas Manyam, Ganiraju C. Tan, Xiaohong Zhang, Hongwei Visco, Carlo Tzankov, Alexandar Dybkaer, Karen Bhagat, Govind Tam, Wayne You, Hua Hsi, Eric D. van Krieken, J. Han Huh, Jooryung Ponzoni, Maurilio Ferreri, Andrés J. M. Møller, Michael B. Piris, Miguel A. Winter, Jane N. Medeiros, Jeffrey T. Xu, Bing Li, Yong Kirsch, Ilan Young, Ken H. |
author_sort | Xu-Monette, Zijun Y. |
collection | PubMed |
description | BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) harbors somatic hypermutation (SHM) in the immunoglobulin heavy chain and light chain variable region genes, IGHV and IGK/LV. Recent studies have revealed that IGV SHM creates neoantigens that activate T-cell responses against B-cell lymphoma. METHODS: To determine the clinical relevance of IGV SHM in DLBCL treated with standard immunochemotherapy, we performed next-generation sequencing of the immunoglobulin variable regions and complementarity determining region 3 (CDR3) for 378 patients with de novo DLBCL. The prognostic effects of IGV SHM and ongoing SHM or intra-clonal heterogeneity were analyzed in the training (192 patients), validation (186 patients), and overall DLBCL cohorts. To gain mechanistic insight, we analyzed the predicted IG-derived neoantigens’ immunogenicity potential, determined by the major histocompatibility complex-binding affinity and the frequency-of-occurrence of T cell-exposed motifs (TCEMs) in a TCEM repertoire derived from human proteome, microbiome, and pathogen databases. Furthermore, IGV SHM was correlated with molecular characteristics of DLBCL and PD-1/L1 expression in the tumor microenvironment assessed by fluorescent multiplex immunohistochemistry. RESULTS: SHM was commonly found in IGHV and less frequently in IGK/LV. High levels of clonal IGHV SHM (SHM(high)) were associated with prolonged overall survival in DLBCL patients, particularly those without BCL2 or MYC translocation. In contrast, long heavy chain CDR3 length, the presence of IGHV ongoing SHM in DLBCL, and high clonal IGK/LV SHM in germinal center B-cell–like (GCB)-DLBCL were associated with poor prognosis. These prognostic effects were significant in both the training and validation sets. By prediction, the SHM(high) groups harbored more potentially immune-stimulatory neoantigens with high binding affinity and rare TCEMs. PD-1/L1 expression in CD8(+) T cells was significantly lower in IGHV SHM(high) than in SHM(low) patients with activated B-cell–like DLBCL, whereas PD-1 expression in CD4(+) T cells and PD-L1 expression in natural killer cells were higher in IGK/LV SHM(high) than in SHM(low) patients with GCB-DLBCL. PD-L1/L2 (9p24.1) amplification was associated with high IGHV SHM and ongoing SHM. CONCLUSIONS: These results show for the first time that IGV SHM(high) and ongoing SHM have prognostic effects in DLBCL and potential implications for PD-1/PD-L1 blockade and neoantigen-based immunotherapies. |
format | Online Article Text |
id | pubmed-6806565 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-68065652019-10-28 Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies Xu-Monette, Zijun Y. Li, Jianyong Xia, Yi Crossley, Beryl Bremel, Robert D. Miao, Yi Xiao, Min Snyder, Thomas Manyam, Ganiraju C. Tan, Xiaohong Zhang, Hongwei Visco, Carlo Tzankov, Alexandar Dybkaer, Karen Bhagat, Govind Tam, Wayne You, Hua Hsi, Eric D. van Krieken, J. Han Huh, Jooryung Ponzoni, Maurilio Ferreri, Andrés J. M. Møller, Michael B. Piris, Miguel A. Winter, Jane N. Medeiros, Jeffrey T. Xu, Bing Li, Yong Kirsch, Ilan Young, Ken H. J Immunother Cancer Research Article BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) harbors somatic hypermutation (SHM) in the immunoglobulin heavy chain and light chain variable region genes, IGHV and IGK/LV. Recent studies have revealed that IGV SHM creates neoantigens that activate T-cell responses against B-cell lymphoma. METHODS: To determine the clinical relevance of IGV SHM in DLBCL treated with standard immunochemotherapy, we performed next-generation sequencing of the immunoglobulin variable regions and complementarity determining region 3 (CDR3) for 378 patients with de novo DLBCL. The prognostic effects of IGV SHM and ongoing SHM or intra-clonal heterogeneity were analyzed in the training (192 patients), validation (186 patients), and overall DLBCL cohorts. To gain mechanistic insight, we analyzed the predicted IG-derived neoantigens’ immunogenicity potential, determined by the major histocompatibility complex-binding affinity and the frequency-of-occurrence of T cell-exposed motifs (TCEMs) in a TCEM repertoire derived from human proteome, microbiome, and pathogen databases. Furthermore, IGV SHM was correlated with molecular characteristics of DLBCL and PD-1/L1 expression in the tumor microenvironment assessed by fluorescent multiplex immunohistochemistry. RESULTS: SHM was commonly found in IGHV and less frequently in IGK/LV. High levels of clonal IGHV SHM (SHM(high)) were associated with prolonged overall survival in DLBCL patients, particularly those without BCL2 or MYC translocation. In contrast, long heavy chain CDR3 length, the presence of IGHV ongoing SHM in DLBCL, and high clonal IGK/LV SHM in germinal center B-cell–like (GCB)-DLBCL were associated with poor prognosis. These prognostic effects were significant in both the training and validation sets. By prediction, the SHM(high) groups harbored more potentially immune-stimulatory neoantigens with high binding affinity and rare TCEMs. PD-1/L1 expression in CD8(+) T cells was significantly lower in IGHV SHM(high) than in SHM(low) patients with activated B-cell–like DLBCL, whereas PD-1 expression in CD4(+) T cells and PD-L1 expression in natural killer cells were higher in IGK/LV SHM(high) than in SHM(low) patients with GCB-DLBCL. PD-L1/L2 (9p24.1) amplification was associated with high IGHV SHM and ongoing SHM. CONCLUSIONS: These results show for the first time that IGV SHM(high) and ongoing SHM have prognostic effects in DLBCL and potential implications for PD-1/PD-L1 blockade and neoantigen-based immunotherapies. BioMed Central 2019-10-22 /pmc/articles/PMC6806565/ /pubmed/31640780 http://dx.doi.org/10.1186/s40425-019-0730-x Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Xu-Monette, Zijun Y. Li, Jianyong Xia, Yi Crossley, Beryl Bremel, Robert D. Miao, Yi Xiao, Min Snyder, Thomas Manyam, Ganiraju C. Tan, Xiaohong Zhang, Hongwei Visco, Carlo Tzankov, Alexandar Dybkaer, Karen Bhagat, Govind Tam, Wayne You, Hua Hsi, Eric D. van Krieken, J. Han Huh, Jooryung Ponzoni, Maurilio Ferreri, Andrés J. M. Møller, Michael B. Piris, Miguel A. Winter, Jane N. Medeiros, Jeffrey T. Xu, Bing Li, Yong Kirsch, Ilan Young, Ken H. Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies |
title | Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies |
title_full | Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies |
title_fullStr | Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies |
title_full_unstemmed | Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies |
title_short | Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies |
title_sort | immunoglobulin somatic hypermutation has clinical impact in dlbcl and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6806565/ https://www.ncbi.nlm.nih.gov/pubmed/31640780 http://dx.doi.org/10.1186/s40425-019-0730-x |
work_keys_str_mv | AT xumonettezijuny immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT lijianyong immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT xiayi immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT crossleyberyl immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT bremelrobertd immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT miaoyi immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT xiaomin immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT snyderthomas immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT manyamganirajuc immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT tanxiaohong immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT zhanghongwei immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT viscocarlo immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT tzankovalexandar immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT dybkaerkaren immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT bhagatgovind immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT tamwayne immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT youhua immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT hsiericd immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT vankriekenjhan immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT huhjooryung immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT ponzonimaurilio immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT ferreriandresjm immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT møllermichaelb immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT pirismiguela immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT winterjanen immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT medeirosjeffreyt immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT xubing immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT liyong immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT kirschilan immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies AT youngkenh immunoglobulinsomatichypermutationhasclinicalimpactindlbclandpotentialimplicationsforimmunecheckpointblockadeandneoantigenbasedimmunotherapies |