Multiple Myeloma Cells Shift the Fate of Cytolytic ILC2s Towards TIGIT-Mediated Cell Death.

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-Kit^hi ILC2s, while levels of DNAM-1 was significantly higher in fully mature c-Kit^lo cells. Among the total MM-associated ILC2s (MM-ILC2s), we observed a significant increase in c-the Kit^lo 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.

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.