Siglec-7 Status Modulates Memory-like Cytotoxicity in Leukemia-Primed Human Natural Killer Cells

Siglec-7 表現調控白血病誘導之自然殺手細胞免疫記憶毒殺功能

自然殺手細胞為免疫系統中清除病毒感染和癌化細胞的第一線防禦，被認為亟具發展為細胞免疫治療的潛能。在病毒感染後，部份存活的自然殺手細胞轉型為記憶型細胞且具更高之毒殺功能，然此記憶型自然殺手細胞的形成機制未明。近日，研究證實病毒感染痊癒後的病患，其周邊血中表現抑制型接受器sialic acid-binding immunoglobulin-like lectins-7 (Siglec-7) 的自然殺手細胞數量顯著不同，且此變化與治療之預後具高度相關性。本研究中，期望探討Siglec-7在白血病細胞誘發記憶過程中的角色，藉由細胞致敏誘導(primed) 作用，分別分析NK-92MI和人類周邊血自然殺手細胞其Siglec-7的表現對記憶形成的影響。我們發現缺乏Siglec-7之NK-92MI細胞，具高度表現AT-rich interactive domain-containing protein 5B (ARID5B) 和高粒線體質量等記憶性特徵。此外，經致敏的NK-92MI細胞對初始致敏白血病細胞具更高之毒殺能力；於周邊血自然殺手細胞的檢測亦呈現相近的結果。更進一步分析Siglec-7表現於致敏作用對記憶性毒殺功能的影響，我們發現僅致敏後Siglec-7_自然殺手細胞具較高之毒殺能力，而Siglec-7+ 細胞的功能甚至低於對照組別。本研究首次驗證Siglec-7的表達影響白血病細胞誘發自然殺手細胞記憶性的形成。

In the immune system, natural killer (NK) cells are known for eliminating viral infected transformed cells and have been explored for their potential in cellular immunotherapy. Following viral infection under an uncharacterized mechanism, some NK cells develop into memory NK cells with featured high cytotoxic activity. During infection, altered population of peripheral sialic acid-binding immunoglobulin-like lectins-7 (Siglec-7)-expressing NK cells are highly correlated with prognosis, indicating the importance of Siglec-7. We aim to investigate the importance of Siglec-7 in leukemia-induced memory. By using two leukemia lysates to separately prime NK-92MI and human peripheral NK cells, we examined how Siglec-7, an inhibitory receptor for cytotoxicity, affects memory-induced cytotoxicity. In this study, the absence of surface Siglec-7 conferred therapeutical NK-92MI memory-like properties, including more expression of AT-rich interactive domain-containing protein 5B (ARID5B) and higher mitochondria mass. Next, by priming NK-92MI cells with two different leukemia lysates, primed cells could respond with increased cytotoxicity against tested leukemia cells. Furthermore, while human peripheral NK cells were obtained and primed, these cells responded similarly to NK-92MI model, displaying elevated cytotoxicity. Surprisingly, after sorting the whole primed NK cells into Siglec-7- and Siglec-7+ populations, only primed Siglec-7- NK cells would exhibit cells characteristic high cytotoxicity, whereas Siglec-7+ ones were even less cytotoxic than resting control NK cells. This finding was the first evidence to suggest that Siglec-7 expression played an important role in NK cytotoxic memory effect for the secondary encounter against leukemia.