Drommi Fabiana, Calabrò Alessia, Pezzino Gaetana, Vento Grazia, Freni Josè, Costa Gregorio, Cavaliere Riccardo, Bonaccorsi Irene, Allegra Alessandro, Ferlazzo Guido, De Pasquale Claudia, Campana Stefania
Laboratory of Immunology and Biotherapy, Department Human Pathology in Adulthood and Childhood "Gaetano Barresi", University of Messina, 98125 Messina, Italy.
Department of Experimental Medicine (DIMES), University of Genoa, 16132 Genova, Italy.
Cancers (Basel). 2025 Jan 15;17(2):263. doi: 10.3390/cancers17020263.
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.
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.
By dissecting ILC2s according to c-Kit marker, we observed that NKp30 and NKG2D were mainly confined to c-Kit ILC2s, while levels of DNAM-1 was significantly higher in fully mature c-Kit cells. Among the total MM-associated ILC2s (MM-ILC2s), we observed a significant increase in c-the Kit subset, 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.
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.
越来越多的证据证明2型固有淋巴细胞（ILC2s）在癌症免疫中具有多方面作用。它们根据肿瘤类型表现出促癌或抗癌活性，但其在多发性骨髓瘤（MM）中的功能仍未阐明。
收集患有MM或癌前疾病患者的骨髓（BM）和外周血（PB），通过流式细胞术评估ILC2亚群的特定特性。
根据c-Kit标志物剖析ILC2s时，我们观察到NKp30和NKG2D主要局限于c-Kit ILC2s，而DNAM-1水平在完全成熟的c-Kit细胞中显著更高。在与MM相关的总ILC2s（MM-ILC2s）中，我们观察到c-Kit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BM中。有趣的是，来自PB的MM-ILC2s表达颗粒酶B（GZMB），但其在BM-ILC2s中的表达受损。因此，MM细胞易被来自PB的MM-ILC2s杀伤，同时在BM中逃避ILC2监视。事实上，在源自BM的MM-ILC2s中，DNAM-1的下调伴随着TIGIT的上调，TIGIT在识别MM细胞表达的同源配体后介导ILC2s中的细胞死亡。这些ILC2变化出现在临床前驱状态，并最终随着疾病进展而累积。
MM-ILC2s可作为在PB中完全有活性的溶细胞免疫效应器。然而，MM细胞通过上调TIGIT使BM中的ILC2命运转向细胞死亡，从而代表恢复ILC2抗肿瘤活性的潜在治疗靶点。
