Alame Melissa, Cornillot Emmanuel, Cacheux Valère, Rigau Valérie, Costes-Martineau Valérie, Lacheretz-Szablewski Vanessa, Colinge Jacques
Institut de Recherche en Cancérologie de Montpellier (IRCM), INSERM U1194, Parc Euromédecine, 208 rue des Apothicaires, 34298 Montpellier, France.
Biological Hematology Department, Montpellier University Hospital, Saint Eloi Hospital, 34275 Montpellier, France.
Theranostics. 2021 Jan 22;11(8):3565-3579. doi: 10.7150/thno.54343. eCollection 2021.
Primary central nervous system diffuse large B-cell lymphoma (PCNSL) is a rare and aggressive entity that resides in an immune-privileged site. The tumor microenvironment (TME) and the disruption of the immune surveillance influence lymphoma pathogenesis and immunotherapy resistance. Despite growing knowledge on heterogeneous therapeutic responses, no comprehensive description of the PCNSL TME is available. We hence investigated the immune subtypes of PCNSL and their association with molecular signaling and survival. Analysis of PCNSL transcriptomes (sequencing, n = 20; microarrays, n = 34). Integrated correlation analysis and signaling pathway topology enabled us to infer intercellular interactions. Immunohistopathology and digital imaging were used to validate bioinformatic results. Transcriptomics revealed three immune subtypes: immune-rich, poor, and intermediate. The immune-rich subtype was associated to better survival and characterized by hyper-activation of STAT3 signaling and inflammatory signaling, , IFNγ and TNF-α, resembling the hot subtype described in primary testicular lymphoma and solid cancer. WNT/β-catenin, HIPPO, and NOTCH signaling were hyper-activated in the immune-poor subtype. HLA down-modulation was clearly associated with a low or intermediate immune infiltration and the absence of T-cell activation. Moreover, HLA class I down-regulation was also correlated with worse survival with implications on immune-intermediate PCNSL that frequently feature reduced HLA expression. A ligand-receptor intercellular network revealed high expression of two immune checkpoints, , CTLA-4/CD86 and TIM-3/LAGLS9. TIM-3 and galectin-9 proteins were clearly upregulated in PCNSL. Altogether, our study reveals that patient stratification according to immune subtypes, HLA status, and immune checkpoint molecule quantification should be considered prior to immune checkpoint inhibitor therapy. Moreover, TIM-3 protein should be considered an axis for future therapeutic development.
原发性中枢神经系统弥漫性大B细胞淋巴瘤（PCNSL）是一种罕见的侵袭性疾病，位于免疫豁免部位。肿瘤微环境（TME）和免疫监视的破坏影响淋巴瘤的发病机制和免疫治疗耐药性。尽管对异质性治疗反应的认识不断增加，但尚无关于PCNSL TME的全面描述。因此，我们研究了PCNSL的免疫亚型及其与分子信号传导和生存的关联。对PCNSL转录组进行分析（测序，n = 20；微阵列，n = 34）。综合相关分析和信号通路拓扑结构使我们能够推断细胞间相互作用。免疫组织病理学和数字成像用于验证生物信息学结果。转录组学揭示了三种免疫亚型：免疫丰富型、免疫贫乏型和中间型。免疫丰富型与更好的生存相关，其特征是STAT3信号传导和炎症信号（IFNγ和TNF-α）的过度激活，类似于原发性睾丸淋巴瘤和实体癌中描述的热亚型。WNT/β-连环蛋白、HIPPO和NOTCH信号在免疫贫乏型中过度激活。HLA下调与低或中等免疫浸润以及T细胞激活的缺乏明显相关。此外，HLA I类下调也与较差的生存相关，这对经常表现出HLA表达降低的免疫中间型PCNSL有影响。一个配体-受体细胞间网络显示两种免疫检查点（CTLA-4/CD86和TIM-3/LAGLS9）的高表达。TIM-3和半乳凝素-9蛋白在PCNSL中明显上调。总之，我们的研究表明，在进行免疫检查点抑制剂治疗之前，应考虑根据免疫亚型、HLA状态和免疫检查点分子定量对患者进行分层。此外，TIM-3蛋白应被视为未来治疗发展的一个轴。
