靶向CD39的乙型肝炎病毒表面蛋白（HBV）陽性CAR-T和個性化的

StephenW

The CD39 positive hepatitis B virus surface protein (HBVs)-targeted CAR-T and personalized tumor-reactive CD8 + T cells exhibit potent anti-hepatocellular carcinoma (HCC) activity
Fan Zou  1 , Jizhou Tan  2 , Ting Liu  2 , Bingfeng Liu  3 , Yaping Tang  4 , Hui Zhang  5 , Jiaping Li  6
Affiliations
Affiliations

    1
    Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510623, China; Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology; Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China.
    2
    Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
    3
    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology; Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China.
    4
    Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510623, China; Department of Neurobiology, Southwest Medical University, Luzhou, Sichuan, 646000, China; Department of Imaging, Affiliated Hospital 3, Zhengzhou University, Zhengzhou 450052, China; Guangdong Provincial Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, China.
    5
    Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, 510080, China; Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology; Key Laboratory of Tropical Disease Control of Ministry of Education, Guangzhou, Guangdong, 510080, China. Electronic address: [email protected].
    6
    Department of Interventional Oncology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China. Electronic address: [email protected].

    PMID: 33484968 DOI: 10.1016/j.ymthe.2021.01.021

Abstract

CD39, expressed by tumor infiltrating lymphocytes (TILs), is a marker to identify tumor-reactive T cells, which is frequently associated with stronger anti-tumor activity than bystander T cells in a variety of malignancies. Therefore, CD39 could be a promising marker for identifying the active anti-tumor immune cells used for cellular immunotherapy. To test this possibility, we constructed the hepatitis B virus surface protein (HBVs)-specific chimeric antigen receptor T-cells (HBVs-CAR-T cells) and generated the personalized tumor-reactive CD8+ T cells. We subsequently assessed their anti-tumor efficiency mainly with a co-culture system for autologous HBVs-positive HCC organoid and T cells. We found that both CD39+ HBVs-CAR-T and CD39+ personalized tumor-reactive CD8+ T cells induced much more apoptosis in HCC organoids. Although the exhaustion status of CAR-T cells increased in CD39+ CAR-T cells, triple knockdown of PD-1, Tim-3, and Lag-3 with shRNAs furtherly enhanced anti-tumor activity in CD39+ CAR-T cells. Furthermore, these CD39+ CAR-T cells exerted an increased secretion of interferon-γ and stronger anti-tumor effect in patient-derived xenograft mouse model. Our findings demonstrated that CD39 could be a promisingly biomarker to enrich active immune cells and become an indicator marker for evaluating the prognosis of immunotherapy for HCC patients.

Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

StephenW

靶向CD39的乙型肝炎病毒表面蛋白（HBV）陽性CAR-T和個性化的腫瘤反應性CD8 + T細胞表現出有效的抗肝細胞癌（HCC）活性
樊鄒1，譚洲州2，劉挺2，劉炳峰3，唐亞平4，慧章5，李嘉平6
隸屬關係
隸屬關係

    1個
    中山大學中山醫學院廣州市婦女兒童醫院廣州兒科研究所，廣東廣州510623；中山大學中山醫學院人類病毒研究所，廣東廣州510080；廣東省抗菌劑與免疫技術工程研究中心；教育部熱帶病控制教育部重點實驗室，廣東廣州510080。
    2
    中山大學附屬第一醫院介入腫瘤科，廣東廣州510080
    3
    中山大學中山醫學院人類病毒研究所，廣東廣州510080；廣東省抗菌劑與免疫技術工程研究中心；教育部熱帶病控制教育部重點實驗室，廣東廣州510080。
    4
    中山大學中山醫學院廣州市婦女兒童醫院廣州兒科研究所，廣東廣州510623；西南醫科大學神經生物學教研室，四川64州646000；鄭州大學第三附屬醫院影像科，鄭州450052；中山大學中山醫學院廣東省腦功能與疾病重點實驗室，廣東廣州510080
    5
    中山大學中山醫學院人類病毒研究所，廣東廣州510080；廣東省抗菌劑與免疫技術工程研究中心；教育部熱帶病控制教育部重點實驗室，廣東廣州510080。電子地址：[email protected]。
    6
    中山大學附屬第一醫院介入腫瘤科，廣東廣州510080電子地址：[email protected]。

    PMID：33484968 DOI：10.1016 / j.ymthe.2021.01.021

抽象

由腫瘤浸潤淋巴細胞（TILs）表達的CD39是鑑定腫瘤反應性T細胞的標誌物，在各種惡性腫瘤中，它通常比旁觀者T細胞具有更強的抗腫瘤活性。因此，CD39可能是鑑定用於細胞免疫療法的活性抗腫瘤免疫細胞的有前途的標誌物。為了測試這種可能性，我們構建了乙型肝炎病毒表面蛋白（HBVs）特異性嵌合抗原受體T細胞（HBVs-CAR-T細胞），並生成了個性化的腫瘤反應性CD8 + T細胞。隨後，我們主要通過自體HBV陽性HCC類器官和T細胞的共培養系統評估了它們的抗腫瘤效率。我們發現CD39 + HBVs-CAR-T和CD39 +個性化的腫瘤反應性CD8 + T細胞在HCC類器官中誘導了更多的細胞凋亡。儘管在CD39 + CAR-T細胞中CAR-T細胞的耗竭狀態有所增加，但PD-1，Tim-3和Lag-3與shRNA的三聯敲低進一步增強了CD39 + CAR-T細胞的抗腫瘤活性。此外，這些CD39 + CAR-T細胞在源自患者的異種移植小鼠模型中發揮了增加的干擾素-γ分泌和更強的抗腫瘤作用。我們的發現表明，CD39可能是富集活性免疫細胞的有前途的生物標誌物，並成為評估HCC患者免疫治療預後的標誌物。

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