Full Text | PDF

Share on tweeters Share on facebook Share on linkedin Share on googleplus

Theranostics 2023; 13(2):458-471. doi:10.7150/thno.78395 This issue Cite

Research Paper

EBV latent membrane protein 1 augments γδ T cell cytotoxicity against nasopharyngeal carcinoma by induction of butyrophilin molecules

Yue Liu1, Ka Sin Lui1, Zuodong Ye1, Tsz Yan Fung1, Luo Chen2, Ping Yiu Sit1, Chin Yu Leung1, Nai Ki Mak1, Ka-Leung Wong2, Hong Lok Lung2, Yoshimasa Tanaka3, Allen Ka Loon Cheung1✉

1. Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR, China.
2. Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR, China.
3. Center for Medical Innovation, Nagasaki University, Nagasaki, Japan.

✉ Corresponding author: Allen KL Cheung; Address: Rm 833, Run Run Shaw Building, Ho Sin-hang campus, Hong Kong Baptist University, 224 Waterloo Road, Kowloon Tong, Hong Kong SAR, China. E-mail: akcheungedu.hk; Tel: (852) 34117745; Fax: (852) 341 More

Citation:
Liu Y, Lui KS, Ye Z, Fung TY, Chen L, Sit PY, Leung CY, Mak NK, Wong KL, Lung HL, Tanaka Y, Cheung AKL. EBV latent membrane protein 1 augments γδ T cell cytotoxicity against nasopharyngeal carcinoma by induction of butyrophilin molecules. Theranostics 2023; 13(2):458-471. doi:10.7150/thno.78395. https://www.thno.org/v13p0458.htm
Other styles

File import instruction

Abstract

Graphic 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 (L2)P4. Effect of (L2)P4 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 P4 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-(L2)P4 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. (L2)P4 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, (L2)P4 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 (L2)P4 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+ tumors.

Keywords: Nasopharyngeal carcinoma, γδ T cells, butyrophilin, NLRC5, EBV latent membrane protein 1 (LMP1)

Citation styles

APA
Liu, Y., Lui, K.S., Ye, Z., Fung, T.Y., Chen, L., Sit, P.Y., Leung, C.Y., Mak, N.K., Wong, K.L., Lung, H.L., Tanaka, Y., Cheung, A.K.L. (2023). EBV latent membrane protein 1 augments γδ T cell cytotoxicity against nasopharyngeal carcinoma by induction of butyrophilin molecules. Theranostics, 13(2), 458-471. https://doi.org/10.7150/thno.78395.

ACS
Liu, Y.; Lui, K.S.; Ye, Z.; Fung, T.Y.; Chen, L.; Sit, P.Y.; Leung, C.Y.; Mak, N.K.; Wong, K.L.; Lung, H.L.; Tanaka, Y.; Cheung, A.K.L. EBV latent membrane protein 1 augments γδ T cell cytotoxicity against nasopharyngeal carcinoma by induction of butyrophilin molecules. Theranostics 2023, 13 (2), 458-471. DOI: 10.7150/thno.78395.

NLM
Liu Y, Lui KS, Ye Z, Fung TY, Chen L, Sit PY, Leung CY, Mak NK, Wong KL, Lung HL, Tanaka Y, Cheung AKL. EBV latent membrane protein 1 augments γδ T cell cytotoxicity against nasopharyngeal carcinoma by induction of butyrophilin molecules. Theranostics 2023; 13(2):458-471. doi:10.7150/thno.78395. https://www.thno.org/v13p0458.htm

CSE
Liu Y, Lui KS, Ye Z, Fung TY, Chen L, Sit PY, Leung CY, Mak NK, Wong KL, Lung HL, Tanaka Y, Cheung AKL. 2023. EBV latent membrane protein 1 augments γδ T cell cytotoxicity against nasopharyngeal carcinoma by induction of butyrophilin molecules. Theranostics. 13(2):458-471.

This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image

©2024 Ivyspring International Publisher. Terms of use