Purpose: Classic Hodgkin lymphoma (cHL) is a B cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the exceptional scarcity (1-5%) of the malignant Hodgkin Reed-Sternberg (HRS) cells within a network of non-malignant immune cells. Molecular determinants governing the relationship between HRS cells and their proximal microenvironment remain largely unknown. Experimental Design: We performed spatially resolved multiplexed protein imaging and transcriptomic sequencing to characterize HRS cell states, cellular neighborhoods, and gene expression signatures of 23.6 million cells from 36 newly diagnosed Epstein-Barr virus (EBV) positive and EBV-negative cHL tumors. Results: We show that MHC-I expression on HRS cells is associated with immune inflamed neighborhoods containing CD8+ T cells, MHC-II+ macrophages, and immune checkpoint expression (i.e., PD-1 and VISTA). We identified spatial clustering of HRS cells, consistent with the syncytial variant of cHL, and its association with T cell excluded neighborhoods in a subset of EBV-negative tumors. Finally, a subset of both EBV-positive and EBV-negative tumors contained regulatory T cells high neighborhoods harboring HRS cells with augmented proliferative capacity. Conclusions: Our study links HRS cell properties with distinct immunophenotypes and potential immune escape mechanisms in cHL.

中文翻译：

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经典霍奇金淋巴瘤霍奇金-里德-斯滕伯格细胞邻域的多重空间分析


目的：经典霍奇金淋巴瘤 (cHL) 是一种 B 细胞淋巴瘤，主要发生于年轻人，较少见于老年人。 cHL 的一个特点是非恶性免疫细胞网络中恶性霍奇金-里德-斯滕伯格 (HRS) 细胞的异常稀缺（1-5%）。控制 HRS 细胞与其近端微环境之间关系的分子决定因素仍然很大程度上未知。实验设计：我们进行了空间分辨多重蛋白质成像和转录组测序，以表征来自 36 个新诊断的 Epstein-Barr 病毒 (EBV) 阳性和 EBV 阴性 cHL 肿瘤的 2360 万个细胞的 HRS 细胞状态、细胞邻域和基因表达特征。结果：我们发现 HRS 细胞上的 MHC-I 表达与含有 CD8+ T 细胞、MHC-II+ 巨噬细胞和免疫检查点表达（即 PD-1 和 VISTA）的免疫炎症区域相关。我们确定了 HRS 细胞的空间聚集，与 cHL 的合胞体变体一致，及其与 EBV 阴性肿瘤子集中排除的 T 细胞邻域的关联。最后，EBV 阳性和 EBV 阴性肿瘤的子集含有调节性 T 细胞高邻域，其中含有增殖能力增强的 HRS 细胞。结论：我们的研究将 HRS 细胞特性与 cHL 中不同的免疫表型和潜在的免疫逃逸机制联系起来。