经典霍奇金淋巴瘤(cHL)中的霍奇金和里德-斯特恩伯格(HRS)细胞积极修饰免疫肿瘤微环境(TME),吸引免疫抑制细胞并表达抑制分子。骨髓细胞在TME中的高频率与不良预后相关。但是更具体和稀有的细胞群缺乏精确的标记。已在cHL患者的外周血中鉴定出髓源性抑制细胞(MDSCs),它们似乎与疾病侵袭性相关。TNFRSF9(CD137)是由单核细胞和树突细胞表达的T细胞共刺激物。其在HRS细胞中的表达也有描述,它被认为在减少抗肿瘤反应中起作用。这里,我们对淋巴细胞和MDSC亚型进行定性和定量分析,并使用多重免疫荧光和自动多光谱成像确定cHL原发肿瘤中CD137细胞的分布.结果与患者的临床特征相关。细胞用特定的免疫检查点标记(PD-1,PD-L1,CD137)染色,肿瘤浸润T淋巴细胞(CD3,PD-1),和单核细胞/MDSC(CD68、CD14、CD33、Arg-1、CD11b)。这种方法使我们能够识别不同的表型,并分析免疫亚群和肿瘤细胞之间的空间相互作用。结果证实CD137表达由T,单核细胞和HRS细胞。此外,CD137的表达,T细胞耗尽,恶性HRS细胞附近的单核细胞MDSCs(m-MDSCs)与预后较差有关。我们的发现揭示了介导免疫逃逸的TME的新元素,并确认CD137是cHL免疫治疗的候选靶标。
表达CD137的免疫细胞和HRS细胞在难治性患者中比在应答者中更丰富且更接近。单核细胞髓源性抑制细胞(m-MDSC)与cHL的不良结果和复发有关,与粒细胞性MDSCs(g-MDSCs)不同,在非应答者中远离HRS细胞。cHL肿瘤微环境通过整体驱动极化和/或募集几种细胞类型并增加CD137和PD-L1检查点的表达来促进难治性患者的免疫逃逸。
The Hodgkin and Reed - Sternberg (HRS) cells in classical Hodgkin Lymphoma (cHL) actively modify the immune tumor microenvironment (TME) attracting immunosuppressive cells and expressing inhibitory molecules. A high frequency of myeloid cells in the TME is correlated with an unfavorable prognosis, but more specific and rare cell populations lack precise markers. Myeloid-derived suppressor cells (MDSCs) have been identified in the peripheral blood of cHL patients, where they appear to be correlated with disease aggressiveness. TNFRSF9 (CD137) is a T cell co-stimulator expressed by monocytic and dendritic cells. Its expression has also been described in HRS cells, where it is thought to play a role in reducing antitumor responses. Here, we perform qualitative and quantitative analyses of lymphocytic and MDSC subtypes and determine the CD137 cell distribution in cHL primary tumors using multiplex immunofluorescence and automated multispectral imaging. The results were correlated with patients\' clinical features. Cells were stained with specific panels of immune checkpoint markers (PD-1, PD-L1, CD137), tumor-infiltrating T lymphocytes (CD3, PD-1), and monocytic cells/MDSCs (CD68, CD14, CD33, Arg-1, CD11b). This approach allowed us to identify distinct phenotypes and to analyze spatial interactions between immune subpopulations and tumor cells. The results confirm CD137 expression by T, monocytic and HRS cells. In addition, the expression of CD137, T exhausted cells, and monocytic MDSCs (m-MDSCs) in the vicinity of malignant HRS cells were associated with a worse prognosis. Our findings reveal new elements of the TME that mediate immune escape, and confirm CD137 as a candidate target for immunotherapy in cHL.
CD137-expressing immune cells and HRS cells are more abundant and in closer proximity in refractory patients than in responders.Monocytic myeloid-derived suppressor cells (m-MDSCs) are associated with unfavorable outcomes and relapse in cHL, unlike granulocytic MDSCs (g-MDSCs), which are located far from HRS cells in non-responders.The cHL tumor microenvironment promotes immune escape in refractory patients by holistically driving polarization and/or recruitment of several cell types with increased expression of CD137 and PD-L1 checkpoints.