2. Academic Validation
  3. EBV promotes TCR-T-cell therapy resistance by inducing CD163+M2 macrophage polarization and MMP9 secretion

EBV promotes TCR-T-cell therapy resistance by inducing CD163+M2 macrophage polarization and MMP9 secretion

  • J Immunother Cancer. 2024 Jun 17;12(6):e008375. doi: 10.1136/jitc-2023-008375.
Yuanyuan Chen # 1 2,  Dijun Ouyang # 1,  Yan Wang # 1,  Qiuzhong Pan 1,  Jingjing Zhao 1,  Hao Chen 1,  Xinyi Yang 1,  Yan Tang 1,  Qijing Wang 1,  Yongqiang Li 1,  Jia He 1,  Jin-Qi You 1,  Yingzi Li 1,  Chi Xu 3,  Yan Ren 3,  Sisi Xie 3,  Song Li 4,  Jiamin Lian 4,  Desheng Weng 5,  Tong Xiang 6,  Jian-Chuan Xia 5
Affiliations

Affiliations

  • 1 Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • 2 Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
  • 3 Knowcell Biotechnology Co., Ltd, Shenzhen, China.
  • 4 TCRCure Biological Technology Co., Ltd, Guangzhou, China.
  • 5 Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China xiajch@mail.sysu.edu.cn xiangtong@sysucc.org.cn wengdsh@sysucc.org.cn.
  • 6 Department of Experimental Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China xiajch@mail.sysu.edu.cn xiangtong@sysucc.org.cn wengdsh@sysucc.org.cn.
  • # Contributed equally.
PMID: 38886114 DOI: 10.1136/jitc-2023-008375
Abstract

Background: Epstein-Barr virus (EBV) is a double-stranded DNA oncogenic virus. Several types of solid tumors, such as nasopharyngeal carcinoma, EBV-associated gastric carcinoma, and lymphoepithelioma-like carcinoma of the lung, have been linked to EBV Infection. Currently, several TCR-T-cell therapies for EBV-associated tumors are in clinical trials, but due to the suppressive immune microenvironment of solid tumors, the clinical application of TCR-T-cell therapy for EBV-associated solid tumors is limited. Figuring out the mechanism by which EBV participates in the formation of the tumor immunosuppressive microenvironment will help T cells or TCR-T cells break through the limitation and exert stronger antitumor potential.

Methods: Flow cytometry was used for analyzing macrophage differentiation phenotypes induced by EBV-infected and EBV-uninfected tumors, as well as the function of T cells co-cultured with these macrophages. Xenograft model in mice was used to explore the effects of M2 macrophages, TCR-T cells, and matrix metalloprotein 9 (MMP9) inhibitors on the growth of EBV-infected tumors.

Results: EBV-positive tumors exhibited an exhaustion profile of T cells, despite the presence of a large T-cell infiltration. EBV-infected tumors recruited a large number of mononuclear macrophages with CCL5 and induced CD163+M2 macrophages polarization through the secretion of CSF1 and the promotion of autocrine IL10 production by mononuclear macrophages. Massive secretion of MMP9 by this group of CD163+M2 macrophages induced by EBV Infection was an important factor contributing to T-cell exhaustion and TCR-T-cell therapy resistance in EBV-positive tumors, and the use of MMP9 inhibitors improved the function of T cells cocultured with M2 macrophages. Finally, the combination of an MMP9 inhibitor with TCR-T cells targeting EBV-positive tumors significantly inhibited the growth of xenografts in mice.

Conclusions: MMP9 inhibitors improve TCR-T cell function suppressed by EBV-induced M2 macrophages. TCR-T-cell therapy combined with MMP9 inhibitors was an effective therapeutic strategy for EBV-positive solid tumors.

Keywords

Head and Neck Neoplasms; Immune Evation; Immunotherapy; Macrophages; Tumor Microenvironment.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-135232
    99.71%, MMP-9 抑制剂
    MMP
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