PD-1 Blockade Can Restore Functions of T-Cells in Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma In Vitro.
PD-1 Blockade Can Restore Functions of T-Cells in Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma In Vitro.
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DOI：
10.1371/journal.pone.0136476
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Liu Y
中科院分区：
文献类型：
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作者：
Quan L;Chen X;Liu A;Zhang Y;Guo X;Yan S;Liu Y
EB病毒阳性弥漫性大B细胞淋巴瘤（EBV+DLBCL）是一种侵袭性恶性肿瘤，对目前的治疗方案具有很大的耐药性，是基于免疫的治疗的有吸引力的靶点。抗程序性死亡-1（PD-1）抗体在临床前模型和晚期实体瘤和血液恶性肿瘤中均显示出令人鼓舞的抗肿瘤作用，但其对EBV+DLBCL的疗效尚不清楚。在此，我们使用T细胞和淋巴瘤细胞系（包括EBV+DLBCL和EBV-DLBCL [包括生发中心B细胞样（GCB）-DLBCL和非GCB-DLBCL]）的共培养系统进行体外实验。我们发现，淋巴瘤细胞增强了PD-1在T细胞上的表达，降低了T细胞的增殖，并改变了多种细胞因子的分泌。然而，通过PD-1阻断，这些功能可以在很大程度上恢复。但PD-1阻断剂对EBV+DLBCL的抗肿瘤免疫效果明显优于EBV-DLBCL。这些结果表明，微环境中的T细胞耗竭和免疫逃逸是DLBCL的潜在机制之一; PD-1阻断可作为EBV+DLBCL的有效免疫治疗。
Epstein–Barr virus-positive diffuse large B-cell lymphoma (EBV+DLBCL) is an aggressive malignancy that is largely resistant to current therapeutic regimens, and is an attractive target for immune-based therapies. Anti-programmed death-1 (PD-1) antibodies showed encouraging anti-tumor effects in both preclinical models and advanced solid and hematological malignancies, but its efficacy against EBV+DLBCL is unknown. Herein, we performed experiments using co-culture system with T cells and lymphoma cell lines including EBV+DLBCL and EBV-DLBCL [including germinal center B-cell like (GCB)-DLBCL and non-GCB-DLBCL] in vitro. We show that lymphoma cells augmented the expression of PD-1 on T cells, decreased the proliferation of T cells, and altered the secretion of multiple cytokines. However, through PD-1 blockade, these functions could be largely restored. Notbaly, the effect of PD-1 blockade on antitumor immunity was more effective in EBV+DLBCL than that in EBV-DLBCL in vitro. These results suggest that T-cell exhaustion and immune escape in microenvironment is one of the mechanisms underlying DLBCL; and PD-1 blockade could present as a efficacious immunotherapeutic treatment for EBV+DLBCL.