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EBV latent membrane protein 1 augments γδ T cell cytotoxicity against nasopharyngeal carcinoma by induction of butyrophilin molecules.
- Source :
-
Theranostics [Theranostics] 2023 Jan 01; Vol. 13 (2), pp. 458-471. Date of Electronic Publication: 2023 Jan 01 (Print Publication: 2023). - Publication Year :
- 2023
-
Abstract
- Nasopharyngeal carcinoma (NPC) is a diverse cancer with no well-defined tumor antigen, associated with oncogenic Epstein-Barr Virus (EBV), and with usually late-stage diagnosis and survival <40%. Current radiotherapy and chemotherapy have low effectiveness and cause adverse effects, which calls for the need of new therapy. In this regard, adoptive immunotherapy using γδ T cells has potential, but needs to be coupled with butyrophilin 2A1 and 3A1 protein expression to achieve tumoricidal effect. Methods: Human γδ T cells were expanded (with Zol or PTA) and used for cytotoxicity assay against NPC cells, which were treated with the EBV EBNA1-targeting peptide (L <subscript>2</subscript> )P <subscript>4</subscript> . Effect of (L <subscript>2</subscript> )P <subscript>4</subscript> on BTN2A1/BTN3A1 expression in NPC cells was examined by flow cytometry and Western blot. An NPC-bearing NSG mice model was established to test the effectiveness of P <subscript>4</subscript> and adoptive γδ T cells. Immunofluorescence was performed on NPC tissue sections to examine the presence of γδ T cells and expression of BTN2A1 and BTN3A1. EBV gene expression post-(L <subscript>2</subscript> )P <subscript>4</subscript> treatment was assessed by qRT-PCR, and the relationship of LMP1, NLRC5 and BTN2A1/BTN3A1 was examined by transfection, reporter assay, Western blot, and inhibition experiments. Results: Zol- or PTA-expanded the Vδ2 subset of γδ T cells that exerted killing against certain NPC cells. (L <subscript>2</subscript> )P <subscript>4</subscript> reactivates latent EBV, which increased BTN2A1 and BTN3A1 expression and conferred higher susceptibility towards Vδ2 T cells cytotoxicity in vitro , as well as enhanced tumor regression in vivo by adoptive transfer of Vδ2 T cells. Mechanistically, (L <subscript>2</subscript> )P <subscript>4</subscript> induced EBV LMP1, leading to IFN-γ/p-JNK and NLRC5 activation, and subsequently stimulated the expression of BTN2A1 and BTN3A1. Conclusions: This study demonstrated the effectiveness of using the EBV-targeting probe (L <subscript>2</subscript> )P <subscript>4</subscript> and adoptive γδ T cells as a promising combinatorial immunotherapy against NPC. The identification of the LMP1-IFN-γ/p-JNK-NLRC5-BTN2A1/BTN3A1 axis may lead to new insight and therapeutic targets against NPC and other EBV <superscript>+</superscript> tumors.<br />Competing Interests: Competing Interests: The authors have declared that no competing interest exists.<br /> (© The author(s).)
- Subjects :
- Animals
Humans
Mice
Antigens, CD
Butyrophilins
Intracellular Signaling Peptides and Proteins
Nasopharyngeal Carcinoma immunology
Nasopharyngeal Carcinoma therapy
Nasopharyngeal Carcinoma virology
Immunotherapy
Epstein-Barr Virus Infections complications
Herpesvirus 4, Human
Nasopharyngeal Neoplasms immunology
Nasopharyngeal Neoplasms therapy
Nasopharyngeal Neoplasms virology
T-Lymphocytes, Cytotoxic
Subjects
Details
- Language :
- English
- ISSN :
- 1838-7640
- Volume :
- 13
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Theranostics
- Publication Type :
- Academic Journal
- Accession number :
- 36632221
- Full Text :
- https://doi.org/10.7150/thno.78395