Integrated Whole Genome and Transcriptome Analysis Identified a Therapeutic Minor Histocompatibility Antigen in a Splice Variant of ITGB2.
| Autor: | Pont MJ; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands., van der Lee DI; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands., van der Meijden ED; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands., van Bergen CA; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands., Kester MG; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands., Honders MW; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands., Vermaat M; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands., Eefting M; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands., Marijt EW; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands., Kielbasa SM; Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands., Hoen PA; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands., Falkenburg JH; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands., Griffioen M; Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands. m.griffioen@lumc.nl. |
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| Jazyk: | angličtina |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2016 Aug 15; Vol. 22 (16), pp. 4185-96. Date of Electronic Publication: 2016 Mar 10. |
| DOI: | 10.1158/1078-0432.CCR-15-2307 |
| Abstrakt: | Purpose: In HLA-matched allogeneic hematopoietic stem cell transplantation (alloSCT), donor T cells recognizing minor histocompatibility antigens (MiHAs) can mediate desired antitumor immunity as well as undesired side effects. MiHAs with hematopoiesis-restricted expression are relevant targets to augment antitumor immunity after alloSCT without side effects. To identify therapeutic MiHAs, we analyzed the in vivo immune response in a patient with strong antitumor immunity after alloSCT. Experimental Design: T-cell clones recognizing patient, but not donor, hematopoietic cells were selected for MiHA discovery by whole genome association scanning. RNA-sequence data from the GEUVADIS project were analyzed to investigate alternative transcripts, and expression patterns were determined by microarray analysis and qPCR. T-cell reactivity was measured by cytokine release and cytotoxicity. Results: T-cell clones were isolated for two HLA-B*15:01-restricted MiHA. LB-GLE1-1V is encoded by a nonsynonymous SNP in exon 6 of GLE1 For the other MiHAs, an associating SNP in intron 3 of ITGB2 was found, but no SNP disparity was present in the normal gene transcript between patient and donor. RNA-sequence analysis identified an alternative ITGB2 transcript containing part of intron 3. qPCR demonstrated that this transcript is restricted to hematopoietic cells and SNP-positive individuals. In silico translation revealed LB-ITGB2-1 as HLA-B*15:01-binding peptide, which was validated as hematopoietic MiHA by T-cell experiments. Conclusions: Whole genome and transcriptome analysis identified LB-ITGB2-1 as MiHAs encoded by an alternative transcript. Our data support the therapeutic relevance of LB-ITGB2-1 and illustrate the value of RNA-sequence analysis for discovery of immune targets encoded by alternative transcripts. Clin Cancer Res; 22(16); 4185-96. ©2016 AACR. (©2016 American Association for Cancer Research.) |
| Databáze: | MEDLINE |
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