Background: Growing evidence attests to the multifaceted roles of group 2 innate lymphoid cells (ILC2s) in cancer immunity. They exhibit either pro- or anticancer activity depending on tumor type but their function in Multiple Myeloma (MM) is still not elucidated. Methods: The bone marrow (BM) and peripheral blood (PB) of patients (pts) with MM or precancerous conditions were collected, and specific properties of ILC2 subsets were assessed by flow cytometry. Results: By dissecting ILC2s according to c-Kit marker, we observed that NKp30 and NKG2D were mainly confined to c-KithiILC2s, while levels of DNAM-1 was significantly higher in fully mature c-Kitlocells. Among the total MM-associated ILC2s (MM-ILC2s), we observed a significant increase in c-the Kitlosubset, but the expression of DNAM-1 in these cells was significantly reduced, especially in BM. Interestingly, MM-ILC2s from PB expressed granzyme B (GZMB), but its expression was impaired in BM-ILC2s. Accordingly, MM cells were susceptible to killing by MM-ILC2s derived from PB while eluding ILC2 surveillance in BM. Indeed, in MM-ILC2s derived from BM, the downregulation of DNAM-1 is accompanied by the upregulation of TIGIT, which mediate cell death in ILC2s upon recognition of the cognate ligands expressed by MM cells. These ILC2 changes appeared in clinical precursor conditions and eventually accumulated with disease progression. Conclusions: MM-ILC2s can act as cytolytic immune effectors that are fully competent in PB. However, MM cells shift ILC2 fate towards cell death in BM via the upregulation of TIGIT, thereby representing a potential therapeutic target to restore ILC2 antitumor activity.
背景：越来越多的证据表明，2型固有淋巴细胞（ILC2s）在癌症免疫中发挥着多方面的作用。根据肿瘤类型的不同，它们表现出促癌或抗癌活性，但在多发性骨髓瘤（MM）中的功能尚未阐明。方法：收集多发性骨髓瘤患者或癌前状态患者的骨髓（BM）和外周血（PB），通过流式细胞术评估ILC2亚群的特异性特征。结果：通过c-Kit标记物分析ILC2s，我们观察到NKp30和NKG2D主要局限于c-Kit高表达ILC2s，而DNAM-1在完全成熟的c-Kit低表达细胞中水平显著更高。在多发性骨髓瘤相关ILC2s（MM-ILC2s）中，我们观察到c-Kit低表达亚群显著增加，但这些细胞中DNAM-1的表达显著降低，尤其是在骨髓中。有趣的是，来自外周血的MM-ILC2s表达颗粒酶B（GZMB），但其在骨髓ILC2s中的表达受损。因此，MM细胞易被来自外周血的MM-ILC2s杀伤，却能在骨髓中逃避ILC2的监视。事实上，在骨髓来源的MM-ILC2s中，DNAM-1的下调伴随着TIGIT的上调，TIGIT在识别MM细胞表达的相应配体后介导ILC2s的细胞死亡。这些ILC2的变化出现在临床前驱状态，并最终随着疾病进展而累积。结论：MM-ILC2s可作为细胞毒性免疫效应细胞，在外周血中完全具备杀伤能力。然而，MM细胞通过上调TIGIT使骨髓中的ILC2s趋向细胞死亡，这为恢复ILC2抗肿瘤活性提供了一个潜在的治疗靶点。
Multiple Myeloma Cells Shift the Fate of Cytolytic ILC2s Towards TIGIT-Mediated Cell Death
肿瘤(癌症)患者之家