Broadening specificity and enhancing cytotoxicity of adoptive T Cells for nasopharyngeal carcinoma immunotherapy

Fae, Damiana Antonia, Martorelli, Debora, Mastorci, Katy, Muraro, Elena, Dal Col, Jessica, Franchin, Giovanni, Barzan, Luigi, Comaro, Elisa, Vaccher, Emanuela, Rosato, Antonio and Dolcetti, Riccardo (2016) Broadening specificity and enhancing cytotoxicity of adoptive T Cells for nasopharyngeal carcinoma immunotherapy. Cancer Immunology Research, 4 5: 431-440. doi:10.1158/2326-6066.CIR-15-0108


Author Fae, Damiana Antonia
Martorelli, Debora
Mastorci, Katy
Muraro, Elena
Dal Col, Jessica
Franchin, Giovanni
Barzan, Luigi
Comaro, Elisa
Vaccher, Emanuela
Rosato, Antonio
Dolcetti, Riccardo
Title Broadening specificity and enhancing cytotoxicity of adoptive T Cells for nasopharyngeal carcinoma immunotherapy
Journal name Cancer Immunology Research   Check publisher's open access policy
ISSN 2326-6066
2326-6074
Publication date 2016-05
Year available 2016
Sub-type Article (original research)
DOI 10.1158/2326-6066.CIR-15-0108
Open Access Status Not Open Access
Volume 4
Issue 5
Start page 431
End page 440
Total pages 10
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Collection year 2017
Language eng
Abstract Although promising, clinical responses to adoptive immunotherapy for nasopharyngeal carcinoma (NPC) are still limited by the restricted number of Epstein-Barr virus (EBV) antigens that can be targeted and their poor immunogenicity. Our previous work indicated that the immunogenic features of the NPC-associated viral antigen BARF1 may be exploited for immunotherapeutic purposes. Nevertheless, T-cell lines obtained with current protocols include only negligible numbers of BARF1-specific cytotoxic T lymphocytes, pointing to the need to enrich these effectors in BARF1 specificities. Considering that in B lymphocytes BARF1 is mainly a lytic EBV antigen, we tested different EBV lytic-cycle inducers (TPA/butyric acid, doxorubicin, and cisplatin) used at suboptimal concentrations for their ability to upregulate BARF1 expression in lymphoblastoid B-cell lines (LCL), the commonly used antigen-presenting cells, without compromising their survival. The LCLs treated with doxo-rubicin (DX-LCL) can reproducibly and efficiently generate EBV-specific effectors enriched in BARF1 specificities from both healthy donors and NPC patients. These DX-LCLs also had more pronounced immunogenic properties, including HLA class I upregulation and expression of immunogenic cell death markers, such as enhanced calreticulin exposure and HMGB1 release. In particular, doxorubicin triggers an HMGB1 autocrine/paracrine loop with its receptor, TLR4, which is also upregulated in DX-LCLs and is responsible for NF-kappa B activation and a delayed apoptosis that allows a prolonged stimulation of EBV-specific T-cell precursors. This protocol may thus constitute a valid alternative to the use of engineered LCLs to generate EBV-specific T-cell lines for adoptive immunotherapy, being relatively simple, easily upgradable to Good Manufacturing Practice standards, and therefore more broadly applicable.
Keyword Epstein-Barr-Virus
Ebv Reactivation
Raji cells
Doxorubicin
Expression
Immunogenicity
Lymphocytes
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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