The CD39(+) HBV surface protein-targeted CAR-T and personalized tumor-reactive CD8(+) T cells exhibit potent anti-HCC activity.
The CD39(+) HBV surface protein-targeted CAR-T and personalized tumor-reactive CD8(+) T cells exhibit potent anti-HCC activity.
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DOI：
10.1016/j.ymthe.2021.01.021
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发表时间：
2021-05-05
期刊：
影响因子：
--
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Zou F;Tan J;Liu T;Liu B;Tang Y;Zhang H;Li J
CD39由肿瘤浸润性淋巴细胞(TILs)表达，是识别肿瘤反应性T细胞的标志，在各种恶性肿瘤中，CD39往往与比旁观者T细胞更强的抗肿瘤活性相关。因此，CD39有望成为细胞免疫治疗中鉴定活性抗肿瘤免疫细胞的一种有前景的标志物。为了验证这种可能性，我们构建了乙肝病毒(乙肝病毒)表面蛋白特异性嵌合抗原受体T细胞(HBVS-CAR-T细胞)，并产生了个性化的肿瘤反应性CD8+T细胞。随后，我们主要通过自体HBV+肝细胞癌类器官和T细胞的共培养系统来评估它们的抗肿瘤效果。我们发现，CD39+HBVS-CAR-T和CD39+个性化肿瘤反应性CD8+T细胞都能诱导更多的肝癌器官细胞凋亡。尽管CD39+CAR-T细胞中CAR-T细胞的耗竭状态增加，但PD-1、TIM-3和LAG-3与shRNA的三重敲除进一步增强了CD39+CAR-T细胞的抗肿瘤活性。此外，在患者来源的异种移植小鼠模型中，这些CD39+CAR-T细胞能够增加干扰素-γ的分泌，并具有更强的抗肿瘤作用。我们的研究结果表明，CD39可能是一种很有前途的生物标志物，可以丰富活跃的免疫细胞，并成为评估肝癌患者免疫治疗预后的指示性标志物。邹某等人。构建了乙肝病毒表面蛋白特异性嵌合抗原受体T细胞(HBVS-CAR-T)，并用肝细胞癌模型和PDX模型评价其抗肿瘤活性。CD39可能是一种很有前景的富含活性CAR-T细胞的生物标志物，而CD39+CAR-T抑制性受体的三倍下调可能会改善肝癌患者的免疫治疗。
CD39, expressed by tumor-infiltrating lymphocytes (TILs), is a marker to identify tumor-reactive T cells, which is frequently associated with stronger antitumor activity than bystander T cells in a variety of malignancies. Therefore, CD39 could be a promising marker for identifying the active antitumor immune cells used for cellular immunotherapy. To test this possibility, we constructed the hepatitis B virus (HBV) surface protein-specific chimeric antigen receptor T cells (HBVs-CAR-T cells) and generated the personalized tumor-reactive CD8+ T cells. We subsequently assessed their antitumor efficiency mainly with a co-culture system for autologous HBVs+ 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 further enhanced antitumor activity in CD39+ CAR-T cells. Furthermore, these CD39+ CAR-T cells exerted an increased secretion of interferon-γ and stronger antitumor effect in a patient-derived xenograft mouse model. Our findings demonstrated that CD39 could be a promising biomarker to enrich active immune cells and become an indicator marker for evaluating the prognosis of immunotherapy for HCC patients. Zou et al. constructed the hepatitis B virus surface protein-specific chimeric antigen receptor T cells (HBVs-CAR-T) and assessed antitumor activity by HCC organoid and PDX model. CD39 may be a promising biomarker to enrich active CAR-T cells, and triple downregulation of inhibitory receptors of CD39+ CAR-T may improve immunotherapy for HCC patients.
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