Academic Journal
Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies
| العنوان: | Immunoglobulin somatic hypermutation has clinical impact in DLBCL and potential implications for immune checkpoint blockade and neoantigen-based immunotherapies |
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| المؤلفون: | Xu-Monette Z. Y., Li J., Xia Y., Crossley B., Bremel R. D., Miao Y., Xiao M., Snyder T., Manyam G. C., Tan X., Zhang H., Visco C., Tzankov A., Dybkaer K., Bhagat G., Tam W., You H., Hsi E. D., Van Krieken J. H., Huh J., Ponzoni M., Ferreri A. J. M., Moller M. B., Piris M. A., Winter J. N., Medeiros J. T., Xu B., Li Y., Kirsch I., Young K. H. |
| المساهمون: | Xu-Monette, Z. Y., Li, J., Xia, Y., Crossley, B., Bremel, R. D., Miao, Y., Xiao, M., Snyder, T., Manyam, G. C., Tan, X., Zhang, H., Visco, C., Tzankov, A., Dybkaer, K., Bhagat, G., Tam, W., You, H., Hsi, E. D., Van Krieken, J. H., Huh, J., Ponzoni, M., Ferreri, A. J. M., Moller, M. B., Piris, M. A., Winter, J. N., Medeiros, J. T., Xu, B., Li, Y., Kirsch, I., Young, K. H. |
| بيانات النشر: | BioMed Central Ltd. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | 9p.24, BCL2, DLBCL, HLA, Immunoglobulin, MHC, Neoantigen, NGS, PD-1, SHM, Adult, Aged, Antigens, Neoplasm, Antineoplastic Agents, Immunological, B7-H1 Antigen, Biomarkers, Tumor, Combined Modality Therapy, Female, Germ-Line Mutation, Humans, Immunotherapy, Lymphoma, Large B-Cell, Diffuse, Male, Middle Aged, Models |
| الوصف: | 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 (SHMhigh) 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 SHMhigh 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 SHMhigh than in SHMlow patients with activated B-cell-like DLBCL, whereas PD-1 ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| Relation: | info:eu-repo/semantics/altIdentifier/wos/WOS:000502261300003; volume:7; issue:1; firstpage:272; journal:JOURNAL FOR IMMUNOTHERAPY OF CANCER; http://hdl.handle.net/20.500.11768/109980 |
| DOI: | 10.1186/s40425-019-0730-x |
| الاتاحة: | https://hdl.handle.net/20.500.11768/109980 https://doi.org/10.1186/s40425-019-0730-x |
| رقم الانضمام: | edsbas.81AAE23C |
| قاعدة البيانات: | BASE |
| DOI: | 10.1186/s40425-019-0730-x |
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