PMID- 29372378 OWN - NLM STAT- MEDLINE DCOM- 20180321 LR - 20181113 IS - 1432-1335 (Electronic) IS - 0171-5216 (Print) IS - 0171-5216 (Linking) VI - 144 IP - 4 DP - 2018 Apr TI - SYK-targeted dendritic cell-mediated cytotoxic T lymphocytes enhance the effect of immunotherapy on retinoblastoma. PG - 675-684 LID - 10.1007/s00432-018-2584-x [doi] AB - PURPOSE: Retinoblastoma (RB) is the most common primary intraocular tumor in children. Chemotherapy is currently the main method of RB treatment. Unfortunately, RB often becomes chemoresistant and turns lethal. Here, we used in vitro cell immunotherapy to explore whether adoptive immunotherapy could be used as a potential treatment for RB. We focused on spleen tyrosine kinase (SYK), which is significantly upregulated in RB cells and serves as a marker for RB cells. METHODS: Using lentiviruses, we genetically modified dendritic cells (DCs) to express and present the SYK peptide antigen to cytotoxic T lymphocytes (CTLs) in vitro. We used SYK-negative cell lines (MDA-MB-231, MCF-10A, and hTERT-RPE1) and SYK-positive cell lines (MCF-7 and RB-Y79) to evaluate the specificity and cytotoxicity of DC presented CTLs using FACS, live-cell imaging, and RNA interference. RESULTS: The cytotoxicity of CTLs induced by SYK-overexpressing DCs (SYK-DC-CTLs) was enhanced more than three times in SYK-positive cell lines compared with SYK-negative cell lines. DCs primed with SYK could drive CTL cytotoxicity against SYK-positive cell lines but not against SYK-negative cell lines. Moreover, SYK-silenced RB-Y79 cells successfully evaded the cytotoxic attack from SYK-DC-CTLs. However, SYK-DC-CTLs could target SYK overexpressed hTERT-RPE1 cells, suggesting that SYK is a specific antigen for RB. Furthermore, SYK-DC-CTL exhibited specific cytotoxicity against carboplatin-resistant RB-Y79 cells in vitro. CONCLUSIONS: Our data showed that SYK could be a potential immunotherapy target mediated by DCs. We propose SYK as a candidate target for treatment of chemoresistant RB. FAU - Chen, Xuemei AU - Chen X AD - The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China. FAU - Kunda, Patricia Elena AU - Kunda PE AD - Centro Investigacion Medicina Traslacional "Severo Amuchastegui" (CIMETSA), Instituto Universitario Ciencias Biomedicas Cordoba (IUCBC), Cordoba, Argentina. FAU - Lin, Jianwei AU - Lin J AD - Shenzhen Key Laboratory for Anti-Ageing and Regenerative Medicine, Health Science Center, Shenzhen University, 3688 Nanhai Avenue, Shenzhen, 518060, Guangdong, China. FAU - Zhou, Meiling AU - Zhou M AD - Shenzhen Key Laboratory for Anti-Ageing and Regenerative Medicine, Health Science Center, Shenzhen University, 3688 Nanhai Avenue, Shenzhen, 518060, Guangdong, China. AD - Department of Biotherapy, Shenzhen Luohu People's Hospital, No. 47 Youyi Road, Shenzhen, 518001, Guangdong, China. FAU - Huang, Jinghan AU - Huang J AD - Department of Biotherapy, Shenzhen Luohu People's Hospital, No. 47 Youyi Road, Shenzhen, 518001, Guangdong, China. FAU - Zhang, Huqin AU - Zhang H AD - The Key Laboratory of Biomedical Information Engineering of Ministry of Education, School of Life Science and Technology, Xi'an Jiaotong University, Xi'an, 710049, China. huqzhang@mail.xjtu.edu.cn. FAU - Liu, Tao AU - Liu T AUID- ORCID: 0000-0002-1199-0076 AD - Shenzhen Key Laboratory for Anti-Ageing and Regenerative Medicine, Health Science Center, Shenzhen University, 3688 Nanhai Avenue, Shenzhen, 518060, Guangdong, China. tao2020@sohu.com. AD - Department of Biotherapy, Shenzhen Luohu People's Hospital, No. 47 Youyi Road, Shenzhen, 518001, Guangdong, China. tao2020@sohu.com. LA - eng GR - No. 61372151/National Natural Science Foundation of China/ GR - No. CXZZ20150324160120260/the Innovation of Science and Technology Commission of Shenzhen/ GR - JCYJ20140417173156100/the Innovation of Science and Technology Commission of Shenzhen/ GR - No. JCYJ20150901164734162/the Innovation of Science and Technology Commission of Shenzhen/ GR - No. GGFW2016030117123665/the Innovation of Science and Technology Commission of Shenzhen/ PT - Journal Article DEP - 20180125 PL - Germany TA - J Cancer Res Clin Oncol JT - Journal of cancer research and clinical oncology JID - 7902060 RN - 0 (Epitopes, T-Lymphocyte) RN - EC 2.7.10.2 (SYK protein, human) RN - EC 2.7.10.2 (Syk Kinase) SB - IM MH - Antigen Presentation MH - Cell Line, Tumor MH - Dendritic Cells/enzymology/*immunology/transplantation MH - Epitopes, T-Lymphocyte/genetics/immunology MH - HEK293 Cells MH - Humans MH - Immunotherapy, Adoptive/*methods MH - Lentivirus/genetics MH - MCF-7 Cells MH - Molecular Targeted Therapy MH - Retinal Neoplasms/enzymology/immunology/*therapy MH - Retinoblastoma/enzymology/immunology/*therapy MH - Syk Kinase/genetics/*immunology MH - T-Lymphocytes, Cytotoxic/*immunology PMC - PMC5843685 OTO - NOTNLM OT - Autologous adoptive immunotherapy OT - Cytotoxic T lymphocytes OT - Dendritic cells OT - Retinoblastoma OT - Spleen tyrosine kinase COIS- CONFLICT OF INTEREST: Author Xuemei Chen has received a fellowship from the National Natural Science Foundation of China. Author Huqin Zhang has received a grant from the National Natural Science Foundation of China (Project No. 61372151). Author Tao Liu has received a grant from the Innovation of Science and Technology Commission of Shenzhen (Project No. CXZZ20150324160120260, No. JCYJ20150901164734162, No. JCYJ20140417173156100, and No. GGFW2016030117123665). Author Xuemei Chen declares that she has no conflict of interest. Author Patricia Elena Kunda declares that she has no conflict of interest. Author Jianwei Lin declares that he has no conflict of interest. Author Meiling Zhou declares that she has no conflict of interest. Author Jinghan Huang declares that he has no conflict of interest. Author Huqin Zhang declares that he has no conflict of interest. Author Tao Liu declares that he has no conflict of interest. ETHICAL APPROVAL: The generation of human DCs and CTLs has been approved by the Ethical Committee of the Shenzhen Luohu People's hospital (ZLNK 03/2015). All blood donors provided written informed consent for the collection of samples and subsequent analysis. EDAT- 2018/01/27 06:00 MHDA- 2018/03/22 06:00 PMCR- 2018/01/25 CRDT- 2018/01/27 06:00 PHST- 2017/10/25 00:00 [received] PHST- 2018/01/15 00:00 [accepted] PHST- 2018/01/27 06:00 [pubmed] PHST- 2018/03/22 06:00 [medline] PHST- 2018/01/27 06:00 [entrez] PHST- 2018/01/25 00:00 [pmc-release] AID - 10.1007/s00432-018-2584-x [pii] AID - 2584 [pii] AID - 10.1007/s00432-018-2584-x [doi] PST - ppublish SO - J Cancer Res Clin Oncol. 2018 Apr;144(4):675-684. doi: 10.1007/s00432-018-2584-x. Epub 2018 Jan 25.