An EBV-related CD4 TCR immunotherapy inhibits tumor growth in an HLA-DP5+nasopharyngeal cancer mouse model
作者全名：Wang, Chenwei; Chen, Jiewen; Li, Jingyao; Xu, Zhihong; Huang, Lihong; Zhao, Qian; Chen, Lei; Liang, Xiaolong; Hu, Hai; Li, Gang; Xiong, Chengjie; Wu, Bin; You, Hua; Du, Danyi; Wang, Xiaoling; Li, Hongle; Wang, Zibing; Chen, Lin
作者地址：[Wang, Chenwei; Chen, Jiewen; Li, Jingyao; Xu, Zhihong; Huang, Lihong; Liang, Xiaolong; Xiong, Chengjie; Wu, Bin; Wang, Xiaoling; Chen, Lin] Guangzhou Med Univ, Guangzhou Med Univ Guangzhou Inst Biomed & Hlth GM, Guangzhou, Guangdong, Peoples R China; [Wang, Chenwei; Chen, Jiewen; Li, Jingyao; Xu, Zhihong; Huang, Lihong; Liang, Xiaolong; Xiong, Chengjie; Wu, Bin; Wang, Xiaoling; Chen, Lin] Guangzhou Med Univ, Guangdong Hong Kong Macau Joint Lab Cell Fate Regu, Guangzhou, Guangdong, Peoples R China; [Zhao, Qian; Chen, Lei] Hong Kong Polytech Univ, Dept Appl Biol & Chem Technol, State Key Lab Chem Biol & Drug Discovery, Hong Kong, Peoples R China; [Chen, Lei] Lab Synthet Chem & Chem Biol Ltd, Hong Kong, Peoples R China; [Hu, Hai] Air Force Hosp Southern Theater Command, Dept Pathol, Guangzhou, Guangdong, Peoples R China; [Li, Gang] Southern Med Univ, Nanfang Hosp, Huiqiao Med Ctr, Dept Otolaryngol Head & Neck Surg, Guangzhou, Guangdong, Peoples R China; [You, Hua] Chongqing Med Univ, Childrens Hosp, Dept Pediat Hematol & Oncol, Lab Excellence Syst Biomed Pediat Oncol, Chongqing, Peoples R China; [Du, Danyi] Southern Med Univ, Nanfang Hosp, Precis Med Ctr, Dept Otolaryngol Head & Neck Surg, Guangzhou, Guangdong, Peoples R China; [Li, Hongle; Wang, Zibing] Zhengzhou Univ, Affiliated Canc Hosp, Dept Immunotherapy, 127 Dongming Rd, Zhengzhou, Henan, Peoples R China; [Li, Hongle; Wang, Zibing] Henan Canc Hosp, 127 Dongming Rd, Zhengzhou, Henan, Peoples R China; [Chen, Lin] Guangzhou Med Univ, Guangzhou Med Univ Guangzhou Inst Biomed & Hlth GM, Guangdong Hong Kong Macau Joint Lab Cell Fate Regu, Guangzhou 511436, Peoples R China
通信作者：Chen, L (通讯作者)，Guangzhou Med Univ, Guangzhou Med Univ Guangzhou Inst Biomed & Hlth GM, Guangzhou, Guangdong, Peoples R China.; Li, HL; Wang, ZB (通讯作者)，Zhengzhou Univ, Affiliated Canc Hosp, Dept Immunotherapy, 127 Dongming Rd, Zhengzhou, Henan, Peoples R China.; Li, HL; Wang, ZB (通讯作者)，Henan Canc Hosp, 127 Dongming Rd, Zhengzhou, Henan, Peoples R China.; Chen, L (通讯作者)，Guangzhou Med Univ, Guangzhou Med Univ Guangzhou Inst Biomed & Hlth GM, Guangdong Hong Kong Macau Joint Lab Cell Fate Regu, Guangzhou 511436, Peoples R China.
来源：JOURNAL OF CLINICAL INVESTIGATION
ESI学科分类：CLINICAL MEDICINE
WOS号：WOS:001208946600024
JCR分区：Q1
影响因子：13.3
年份：2024
卷号：134
期号：8
开始页：
结束页：
文献类型：Article
关键词：
摘要：Adoptive transfer of T cell receptor-engineered T cells (TCR-T) is a promising strategy for immunotherapy against solid tumors. However, the potential of CD4+ T cells in mediating tumor regression has been neglected. Nasopharyngeal cancer is consistently associated with EBV. Here, to evaluate the therapeutic potential of CD4 TCR-T in nasopharyngeal cancer, we screened for CD4 TCRs recognizing EBV nuclear antigen 1 (EBNA1) presented by HLA-DP5. Using mass spectrometry, we identified EBNA1567-581, a peptide naturally processed and presented by HLA-DP5. We isolated TCR135, a CD4 TCR with high functional avidity, that can function in both CD4+ and CD8+ T cells and recognizes HLA-DP5-restricted EBNA1567-581. TCR135transduced T cells functioned in two ways: directly killing HLA-DP5+EBNA1+ tumor cells after recognizing EBNA1 presented by tumor cells and indirectly killing HLA-DP5-negative tumor cells after recognizing EBNA1 presented by antigen -presenting cells. TCR135-transduced T cells preferentially infiltrated into the tumor microenvironment and significantly inhibited tumor growth in xenograft nasopharyngeal tumor models. Additionally, we found that 62% of nasopharyngeal cancer patients showed 50%-100% expression of HLA-DP on tumor cells, indicating that nasopharyngeal cancer is well suited for CD4 TCR-T therapy. These findings suggest that TCR135 may provide a new strategy for EBV-related nasopharyngeal cancer immunotherapy in HLA-DP5+ patients.
基金机构：National Natural Science Foundation of China [81903156, 81972690]; Guangzhou Basic and Applied Basic Research Foundation [2023A04J1176]; Henan Provincial Department of Science and Technology [222300420574]; Health Commission of Henan Province [YXKC2021007, SBGJ20211008]; Research Grants Council-CRF Equipment [C5033-19E]; Laboratory for Synthetic Chemistry and Chemical Biology Limited.
基金资助正文：This study was supported by the National Natural Science Foundation of China (81903156 and 81972690) , Guangzhou Basic and Applied Basic Research Foundation (2023A04J1176) , Henan Provincial Department of Science and Technology (222300420574) , Health Commission of Henan Province (YXKC2021007 and SBGJ20211008) , Research Grants Council-CRF Equipment C5033-19E, and Laboratory for Synthetic Chemistry and Chemical Biology Limited under the Health@InnoHK Program launched by Innovation and Technology Commission, Hong Kong. We thank comPing Li for her help with flow cytometry cell sorting. We thank Gene Denovo Biotechnology Co. Ltd. (Guangzhou, China) for the sequencing platform and bioinformatics analysis. We thank Heng Liu for helping with the 3D protein structure illustration. We thank Brian Till, Lai Wei, and Xiaoren Zhang for helpful discussion
