Chantziou Amanda, Brenna Cloe, Ioannidou Kalliopi, Chen Oliver Y, Korkolopoulou Penelope, Antoniadou Anastasia, Psichogiou Mina, Papaioannou Maria, Tsirigotis Panagiotis, Foukas Periklis G, de Leval Laurence, Petrovas Constantinos
Department of Laboratory Medicine and Pathology, Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland.
Department of Laboratory Medicine and Pathology, Lausanne University Hospital and Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Blood Adv. 2024 Dec 24;8(24):6215-6231. doi: 10.1182/bloodadvances.2023012116.
The impact of HIV infection on the tumor microenvironment (TME) of classic Hodgkin lymphoma (cHL), one of the most common comorbidities after HIV infection, is not well understood. Here, we have used multiplexed immunofluorescence and spatial transcriptomic analysis to dissect the impact of viral infections (Epstein-Barr virus [EBV] and HIV/EBV) on cHL TME. HIV-EBV+ cHL TME was characterized by higher cell densities of CD8high T cells coexpressing inhibitory receptors (PD-1 and TIGIT), macrophage subsets, and an in situ inflammatory molecular profile associated with increased expression of T-cell receptor (TCR) and B-cell receptor cell signaling pathways than HIV-EBV- cHL TME. Compared with HIV-EBV+, HIV+EBV+ cHL TME was characterized by significantly less CD8high T cells coexpressing PD-1 and TIGIT, a profile concomitant with significantly increased cell densities of CD155high neoplastic cells. Significant downregulation of in situ TCR signaling and upregulation of extracellular matrix reorganization pathways were found in HIV+EBV+ cHL TME, in line with an altered topological organization of CXCL13 and heparan sulfate, an extracellular matrix glycosaminoglycan. Our data reveal the complexity of the cellular and molecular composition of cHL TME in the presence of viral infections, with possible implications for combinatorial immunotherapies. Furthermore, the data suggest specific molecular targets and pathways for further investigation that could improve our understanding of possible mechanistic links between HIV and lymphomagenesis.
HIV感染对经典型霍奇金淋巴瘤（cHL）肿瘤微环境（TME）的影响尚未完全明确，而cHL是HIV感染后最常见的合并症之一。在此，我们运用多重免疫荧光和空间转录组分析来剖析病毒感染（爱泼斯坦-巴尔病毒[EBV]以及HIV/EBV）对cHL TME的影响。与HIV-EBV- cHL TME相比，HIV-EBV+ cHL TME的特征在于共表达抑制性受体（PD-1和TIGIT）的CD8高表达T细胞、巨噬细胞亚群的细胞密度更高，以及与T细胞受体（TCR）和B细胞受体细胞信号通路表达增加相关的原位炎症分子谱。与HIV-EBV+相比，HIV+EBV+ cHL TME的特征是共表达PD-1和TIGIT的CD8高表达T细胞显著减少，这一特征与CD155高表达肿瘤细胞的细胞密度显著增加相伴。在HIV+EBV+ cHL TME中发现原位TCR信号显著下调以及细胞外基质重组途径上调，这与CXCL13和硫酸乙酰肝素（一种细胞外基质糖胺聚糖）的拓扑结构改变一致。我们的数据揭示了病毒感染情况下cHL TME细胞和分子组成的复杂性，这可能对联合免疫疗法具有启示意义。此外，数据还提示了特定的分子靶点和途径以供进一步研究，这可能增进我们对HIV与淋巴瘤发生之间可能的机制联系的理解。
