Quan Lina, Lan Xiuwen, Meng Yuanyuan, Guo Xiuchen, Guo Yiwei, Zhao Lina, Chen Xue, Liu Aichun
Department of Hematology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China.
Gastroenterological Department, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang Province, China.
Exp Hematol. 2018 Apr;60:47-56.e1. doi: 10.1016/j.exphem.2018.01.003. Epub 2018 Feb 3.
Immunotherapy results in lymphoma have been encouraging. Preclinical and clinical trials have proven checkpoint blockade, such as PD-1 antibody, as an effective treatment for lymphoma, including diffuse large B-cell lymphoma (DLBCL). Combination of checkpoint blockades has emerged as a new way to treat lymphoma; however, the status of checkpoint expression and their function in DLBCL have not been fully elucidated yet. In this study, we examined the expression of BTLA, PD-1, TIM-3, LIGHT, and LAG-3 in tumor microenvironmental T cells of DLBCL using flow cytometry and compared the cytotoxicity and differentiation status of BTLA and BTLA T-cells. We further characterized the relationship of STAT3 phosphorylation (p-STAT3) with BTLA expression. Our results suggest that BTLA T cells highly express other checkpoint molecules, including PD-1, TIM-3, LIGHT, and LAG-3. Moreover, high expression of BTLA is correlated with advanced stage of DLBCL. BTLA T cells have a less-differentiated phenotype, lower cytolytic function, and higher potential to proliferate compared with BTLA T cells. Taken together, our data provide the first evidence that increased BTLA predicts poor prognosis in patients with DLBCL, and blockade of BTLA with other checkpoints may potentially represent a new strategy for immunotherapy of DLBCL.
免疫疗法在淋巴瘤治疗中的效果令人鼓舞。临床前和临床试验已证明，诸如PD-1抗体之类的检查点阻断剂是治疗淋巴瘤（包括弥漫性大B细胞淋巴瘤（DLBCL））的有效方法。联合使用检查点阻断剂已成为治疗淋巴瘤的一种新方法；然而，DLBCL中检查点的表达状态及其功能尚未完全阐明。在本研究中，我们使用流式细胞术检测了DLBCL肿瘤微环境T细胞中BTLA、PD-1、TIM-3、LIGHT和LAG-3的表达，并比较了BTLA和BTLA T细胞的细胞毒性和分化状态。我们进一步研究了STAT3磷酸化（p-STAT3）与BTLA表达之间的关系。我们的结果表明，BTLA T细胞高表达其他检查点分子，包括PD-1、TIM-3、LIGHT和LAG-3。此外，BTLA的高表达与DLBCL的晚期阶段相关。与BTLA T细胞相比，BTLA T细胞具有分化程度较低的表型、较低的细胞溶解功能和较高的增殖潜力。综上所述，我们的数据首次证明，BTLA表达增加预示着DLBCL患者预后不良，阻断BTLA与其他检查点可能代表一种新的DLBCL免疫治疗策略。
