BLS 型弥漫性大 B 细胞淋巴瘤中 PD-L1 的频繁表达：对侵袭性和免疫治疗的影响。

Frequent expression of PD-L1 in BLS-type diffuse large B-cell lymphoma: implications for aggressiveness and immunotherapy.

机构信息

Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.

Department of Pathology, School of Medicine, Chung Shan Medical University, Taichung, Taiwan; Department of Pathology, Chung Shan Medical University Hospital, Taichung, Taiwan.

出版信息

Pathology. 2024 Apr;56(3):367-373. doi: 10.1016/j.pathol.2023.10.019. Epub 2024 Jan 14.

DOI:10.1016/j.pathol.2023.10.019

PMID:38290893

Abstract

BLS-type diffuse large B-cell lymphoma (DLBCL) denotes an uncommon, aggressive variant of DLBCL presenting initially in bone marrow, liver and spleen without lymphadenopathy or mass lesion. Patients with BLS-type DLBCL present frequently with haemophagocytic syndrome which often leads to early patient demise. Programmed death ligand 1 (PD-L1) plays a negative regulatory role on effector T cells and is an important target of immunotherapy. Assessment of PD-L1 expression in BLS-type DLBCL may carry therapeutic implications and provide mechanistic insights. Standard immunohistochemical analysis for PD-L1 was performed in seven cohorts for this study: (1) DLBCL-not otherwise specified (NOS) (n=201); (2) Epstein-Barr virus (EBV)-positive DLBCL (n=26); (3) thymic (primary mediastinal) DLBCL (n=12); (4) intravascular LBCL (n=3); (5) high-grade B-cell lymphoma, NOS (n=12); (6) BLS-type DLBCL (n=37); and (7) systemic DLBCL involving bone marrow (n=28). We found that PD-L1 was positive in 12.9% of DLBCL-NOS cases, 46.2% of EBV-positive DLBCL, 91.7% of thymic LBCL, none of intravascular LBCL, 8.3% of high-grade B-cell lymphoma-NOS, and 56.8% of BLS-type DLBCL. By comparison, only 14.3% of bone marrow cases involved by systemic DLBCL were positive for PD-L1 (p<0.001). Interestingly, BLS-type DLBCL more frequently showed activated B-cell phenotype (86.5% vs 65.2%, p=0.010), a high Ki-67 proliferative index (97.1% vs 63.3%, p<0.001), MYC overexpression (90.9% vs 56.2%, p=0.023), presence of haemophagocytic syndrome (86.5% vs 4.0%, p<0.001), and poorer overall survival (p<0.001) than DLBCL-NOS. These data suggest that the poor prognosis of BLS-type DLBCL may be explained by both extrinsic tumour microenvironment factors and intrinsic genetic factors of tumour cells, such as PD-L1-associated inactivation of anti-tumour immunity for the former, and MYC pathway activation-related aggressiveness for the latter.

摘要

BLS 型弥漫性大 B 细胞淋巴瘤（DLBCL）表示一种罕见的侵袭性 DLBCL 变体，最初表现为骨髓、肝脏和脾脏受累，而无淋巴结病或肿块病变。BLS 型 DLBCL 患者常表现为噬血细胞综合征，这往往导致患者早期死亡。程序性死亡配体 1（PD-L1）在效应 T 细胞上发挥负性调节作用，是免疫治疗的重要靶点。评估 BLS 型 DLBCL 中 PD-L1 的表达可能具有治疗意义，并提供机制见解。本研究对 7 个队列的 BLS 型 DLBCL 进行了 PD-L1 的标准免疫组化分析：（1）非特指性弥漫性大 B 细胞淋巴瘤（DLBCL-NOS）（n=201）；（2）EB 病毒阳性（EBV）DLBCL（n=26）；（3）胸内（原发性纵隔）DLBCL（n=12）；（4）血管内大 B 细胞淋巴瘤（n=3）；（5）高级别 B 细胞淋巴瘤-NOS（n=12）；（6）BLS 型 DLBCL（n=37）；（7）骨髓累及的系统性 DLBCL（n=28）。我们发现，DLBCL-NOS 病例中 PD-L1 阳性率为 12.9%，EBV 阳性 DLBCL 为 46.2%，胸内 DLBCL 为 91.7%，血管内大 B 细胞淋巴瘤为 0%，高级别 B 细胞淋巴瘤-NOS 为 8.3%，BLS 型 DLBCL 为 56.8%。相比之下，骨髓累及的系统性 DLBCL 中仅有 14.3%的病例 PD-L1 阳性（p<0.001）。有趣的是，BLS 型 DLBCL 更常表现为活化 B 细胞表型（86.5%比 65.2%，p=0.010）、高 Ki-67 增殖指数（97.1%比 63.3%，p<0.001）、MYC 过表达（90.9%比 56.2%，p=0.023）、噬血细胞综合征（86.5%比 4.0%，p<0.001）和总体生存率较差（p<0.001）。这些数据表明，BLS 型 DLBCL 的不良预后可能是由肿瘤细胞的外在肿瘤微环境因素和内在遗传因素共同解释的，前者是 PD-L1 相关的抗肿瘤免疫失活，后者是 MYC 通路激活相关的侵袭性。