Brandetti Elisa, Focaccetti Chiara, Pezzolo Annalisa, Ognibene Marzia, Folgiero Valentina, Cotugno Nicola, Benvenuto Monica, Palma Paolo, Manzari Vittorio, Rossi Paolo, Fruci Doriana, Bei Roberto, Cifaldi Loredana
Academic Department of Pediatrics (DPUO), Ospedale Pediatrico Bambino Gesù, IRCCS, 00165 Rome, Italy.
Department of Human Science and Promotion of the Quality of Life, San Raffaele Roma Open University, 00166 Rome, Italy.
Cancers (Basel). 2021 Aug 29;13(17):4368. doi: 10.3390/cancers13174368.
High-risk neuroblastoma (NB) is a rare childhood cancer whose aggressiveness is due to a variety of chromosomal genetic aberrations, including those conferring immune evasion. Indeed, NB cells adopt several molecular strategies to evade recognition by the immune system, including the downregulation of ligands for NK-cell-activating receptors. To date, while molecular strategies aimed at enhancing the expression of ligands for NKG2D- and DNAM-1-activating receptors have been explored, no evidence has been reported on the immunomodulatory mechanisms acting on the expression of death receptors such as Fas in NB cells. Here, we demonstrated that transient overexpression of the NF-kB p65 subunit upregulates the surface expression of Fas and PVR, the ligand of DNAM-1, thus making NB cell lines significantly more susceptible to NK-cell-mediated apoptosis, recognition, and killing. In contrast, IFNγ and TNFα treatment, although it induced the upregulation of FAS in NB cells and consequently enhanced NK-cell-mediated apoptosis, triggered immune evasion processes, including the strong upregulation of MHC class I and IDO1, both of which are involved in mechanisms leading to the impairment of a proper NK-cell-mediated killing of NB. In addition, high-resolution array CGH analysis performed in our cohort of NB patients revealed that the loss of and/or genes correlated with low survival independently of the disease stage. Our data identify the status of the and genes as prognostic biomarkers of NB that may predict the efficacy of NK-cell-based immunotherapy of NB. Overall, restoration of surface expression of Fas and PVR, through transient upregulation of NF-kB, may be a clue to a novel NK-cell-based immunotherapy of NB.
高危神经母细胞瘤（NB）是一种罕见的儿童癌症，其侵袭性归因于多种染色体遗传畸变，包括那些赋予免疫逃逸能力的畸变。事实上，NB细胞采用多种分子策略来逃避免疫系统的识别，包括下调自然杀伤细胞（NK细胞）激活受体的配体。迄今为止，虽然已经探索了旨在增强NKG2D和DNAX辅助分子-1（DNAM-1）激活受体配体表达的分子策略，但尚未有关于作用于NB细胞中死亡受体（如Fas）表达的免疫调节机制的报道。在此，我们证明，核因子κB（NF-κB）p65亚基的瞬时过表达上调了Fas和DNAM-1的配体脊髓灰质炎病毒受体（PVR）的表面表达，从而使NB细胞系对NK细胞介导的凋亡、识别和杀伤显著更敏感。相比之下，干扰素γ（IFNγ）和肿瘤坏死因子α（TNFα）处理虽然诱导了NB细胞中FAS的上调并因此增强了NK细胞介导的凋亡，但引发了免疫逃逸过程，包括主要组织相容性复合体I类分子（MHC I类分子）和吲哚胺2,3-双加氧酶1（IDO1）的强烈上调，这两者都参与导致NK细胞对NB的杀伤功能受损的机制。此外，在我们的NB患者队列中进行的高分辨率阵列比较基因组杂交（array CGH）分析显示， 和/或 基因的缺失与低生存率相关，且与疾病分期无关。我们的数据确定了 和 基因的状态作为NB的预后生物标志物，可能预测基于NK细胞的NB免疫疗法的疗效。总体而言，通过NF-κB的瞬时上调恢复Fas和PVR的表面表达，可能是一种新型的基于NK细胞的NB免疫疗法的线索。
