Barberi Chiara, De Pasquale Claudia, Allegra Alessandro, Sidoti Migliore Giacomo, Oliveri Daniela, Loiacono Fabrizio, Innao Vanessa, Musolino Caterina, Pende Daniela, Cantoni Claudia, Carrega Paolo, Mingari Maria Cristina, Campana Stefania, Ferlazzo Guido
Department of Experimental Medicine (DIMES) and.
Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy.
Blood Adv. 2020 May 26;4(10):2297-2307. doi: 10.1182/bloodadvances.2019000953.
Natural killer (NK) cells represent innate effector cells potentially able to play a role during the immune response against multiple myeloma (MM). To better define the distribution and the specific properties of NK cell subsets during MM disease, we analyzed their features in the bone marrow and peripheral blood of newly diagnosed MM patients. Our findings revealed that, in both compartments, NK cells were more abundant than in healthy donors. Among total MM-NK cells, a significant increase of CD94lowCD56dim NK cell subset was observed, which already appears in clinical precursor conditions leading to MM, namely monoclonal gammopathy of undetermined significance and smoldering MM, and eventually accumulates with disease progression. Moreover, a consistent fraction of CD94lowCD56dim NK cells was in a proliferation phase. When analyzed for their killing abilities, they represented the main cytotoxic NK cell subset against autologous MM cells. In vitro, MM cells could rapidly induce the expansion of the CD94lowCD56dim NK cell subset, thus reminiscent of that observed in MM patients. Mechanistically, this accumulation relied on cell to cell contacts between MM and NK cells and required both activation via DNAM-1 and homophilic interaction with CD56 expressed on MM cells. Considering the growing variety of combination treatments aimed at enhancing NK cell-mediated cytotoxicity against MM, these results may also be informative for optimizing current immunotherapeutic approaches.
自然杀伤（NK）细胞是先天性效应细胞，在针对多发性骨髓瘤（MM）的免疫反应中可能发挥作用。为了更好地定义MM疾病期间NK细胞亚群的分布和特定特性，我们分析了新诊断MM患者骨髓和外周血中的NK细胞特征。我们的研究结果显示，在这两个部位，NK细胞都比健康供体中的更为丰富。在总的MM-NK细胞中，观察到CD94lowCD56dim NK细胞亚群显著增加，该亚群在导致MM的临床前驱病症即意义未明的单克隆丙种球蛋白病和冒烟型MM中就已出现，并最终随着疾病进展而积累。此外，相当一部分CD94lowCD56dim NK细胞处于增殖阶段。当分析其杀伤能力时，它们是针对自体MM细胞的主要细胞毒性NK细胞亚群。在体外，MM细胞可迅速诱导CD94lowCD56dim NK细胞亚群的扩增，这与在MM患者中观察到的情况相似。从机制上讲，这种积累依赖于MM细胞与NK细胞之间的细胞间接触，并且需要通过DNAM-1激活以及与MM细胞上表达的CD56进行同源相互作用。考虑到旨在增强NK细胞介导的针对MM的细胞毒性的联合治疗方法日益增多，这些结果可能也有助于优化当前的免疫治疗方法。
