Kobayashi Hiroki, Chijimatsu Ryota, Naoi Yusuke, Otani Yoshihiro, Mizuta Ryo, Fujii Kentaro, Ishida Joji, Murakami Hiroyuki, Ujiie Hideki, Ikeuchi Kazuhiro, Urata Tomohiro, Seike Keisuke, Fujiwara Hideaki, Asada Noboru, Fujii Nobuharu, Matsuoka Ken-Ichi, Sato Yasuharu, Maeda Yoshinobu, Ennishi Daisuke
Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama, Japan.
Blood Neoplasia. 2024 Nov 15;2(1):100058. doi: 10.1016/j.bneo.2024.100058. eCollection 2025 Feb.
Primary central nervous system lymphoma (PCNSL) is a rare, aggressive type of lymphoma, most often histologically diagnosed as diffuse large B-cell lymphoma (DLBCL). Recent advancements in single-cell sequencing have elucidated that the diverse germinal center states in systemic DLBCL manifest as tumor cell diversity, intricately linked to variations in the microenvironment. However, detailed characterization of intratumoral heterogeneity reflecting B-cell states in PCNSL remains elusive. Here, we conducted single-cell and spatial multiomic analyses to elucidate the cellular and spatial heterogeneity and the microenvironment in PCNSL. We identified a distinctive lymphoma subpopulation with gene and protein expression similar to that of plasmablasts (PBLs), enriched in some patients with PCNSL. B-cell receptor (BCR) analysis revealed that BCR clonotypes of the PBL signature subpopulation were shared with other subpopulations, suggesting a common origin with other lymphoma cell subtypes. Spatial analysis additionally revealed several localization patterns of PBL signature subpopulations within the tissue, indicating spatial heterogeneity. An expansion study showed that ∼40% of patients with PCNSL had a PBL signature subpopulation, as defined by CD138 immunohistochemistry staining. Additionally, patients with a PBL signature subpopulation and low CD3 cell infiltration exhibited a worse prognosis. Finally, intercellular communication analysis suggested that the PBL signature subpopulation had distinct cellular interactions with the microenvironment. In summary, our study identified a tumor subpopulation with a PBL signature in PCNSL, suggesting distinct molecular and spatial cross talk with the microenvironment. These findings provided new insights into the biological mechanisms of PCNSL.
原发性中枢神经系统淋巴瘤（PCNSL）是一种罕见的侵袭性淋巴瘤，组织学上大多诊断为弥漫性大B细胞淋巴瘤（DLBCL）。单细胞测序的最新进展表明，系统性DLBCL中不同的生发中心状态表现为肿瘤细胞多样性，与微环境的变化密切相关。然而，反映PCNSL中B细胞状态的肿瘤内异质性的详细特征仍不清楚。在此，我们进行了单细胞和空间多组学分析，以阐明PCNSL中的细胞和空间异质性以及微环境。我们鉴定出一个独特的淋巴瘤亚群，其基因和蛋白质表达与浆母细胞（PBL）相似，在一些PCNSL患者中富集。B细胞受体（BCR）分析显示，PBL特征亚群的BCR克隆型与其他亚群共享，表明与其他淋巴瘤细胞亚型有共同起源。空间分析还揭示了PBL特征亚群在组织内的几种定位模式，表明存在空间异质性。一项扩展研究表明，约40%的PCNSL患者有PBL特征亚群，由CD138免疫组化染色定义。此外，有PBL特征亚群且CD3细胞浸润低的患者预后较差。最后，细胞间通讯分析表明，PBL特征亚群与微环境有独特的细胞相互作用。总之，我们的研究在PCNSL中鉴定出一个具有PBL特征的肿瘤亚群，提示与微环境有独特的分子和空间相互作用。这些发现为PCNSL的生物学机制提供了新的见解。
