The Division of Gastrointestinal Surgery, Wuhan Fourth Hospital (Tongji Medical College Affiliated Wuhan Puai Hospital), 473 Hanzheng Street, Qiaokou District, Wuhan, Hubei Province 430033, China.
The Division of Gastrointestinal Surgery, Wuhan Fourth Hospital (Tongji Medical College Affiliated Wuhan Puai Hospital), 473 Hanzheng Street, Qiaokou District, Wuhan, Hubei Province 430033, China.
Mol Immunol. 2023 Jun;158:68-78. doi: 10.1016/j.molimm.2023.04.011. Epub 2023 May 3.
The immune system plays a crucial role in controlling colorectal cancer (CRC) development. Natural killer (NK) cells are tumoricidal but undergo exhaustion in CRC patients. The current research aims to understand the role of sirtuin 6 (SIRT6) in CRC-associated NK cell exhaustion in a murine inflammatory colorectal cancer model. To this end, inflammatory CRC was induced by treating mice with azoxymethane plus dextran sulfate sodium. The expression of SIRT6 in NK cells in murine mesenteric lymph nodes (mLNs) and the CRC tissue was characterized by Immunoblotting. SIRT6 knockdown was achieved by lentiviral transduction of murine splenic NK cells, followed by evaluation of NK cell proliferation and the expression of cytotoxic mediators using flow cytometry. NK cell cytotoxicity was measured by cytotoxicity assays. Adoptive transfer of murine NK cells was applied to analyze the effect of SIRT6 knockdown in vivo. We found that SIRT6 was up-regulated in infiltrating NK cells in the murine CRC tissue, especially NK cells with an exhausted phenotype and impaired cytotoxicity. SIRT6 knockdown significantly boosted murine splenic NK cell functionality, as evidenced by accelerated proliferation, increased production of cytotoxic mediators, and higher tumoricidal activity both in vitro and in vivo. Furthermore, the adoptive transfer of SIRT6-knockdown NK cells into CRC-bearing mice effectively suppressed CRC progression. Therefore, SIRT6 up-regulation is essential for murine NK cell exhaustion in CRC because it impedes the tumoricidal activity of murine NK cells. Artificial SIRT6 down-regulation could boost the function of infiltrating NK cells to oppress CRC progression in mice.
免疫系统在控制结直肠癌（CRC）发展中起着至关重要的作用。自然杀伤（NK）细胞具有杀伤肿瘤的作用，但在 CRC 患者中会发生衰竭。目前的研究旨在了解 Sirtuin 6（SIRT6）在小鼠炎症性结直肠癌模型中与 CRC 相关的 NK 细胞衰竭中的作用。为此，通过用氧化偶氮甲烷加葡聚糖硫酸钠处理小鼠来诱导炎症性 CRC。通过免疫印迹法对小鼠肠系膜淋巴结（mLN）和 CRC 组织中的 NK 细胞中的 SIRT6 表达进行了表征。通过慢病毒转导小鼠脾 NK 细胞实现 SIRT6 敲低，然后通过流式细胞术评估 NK 细胞增殖和细胞毒性介质的表达。通过细胞毒性测定测量 NK 细胞的细胞毒性。应用 NK 细胞过继转移来分析体内 SIRT6 敲低的效果。我们发现 SIRT6 在小鼠 CRC 组织中浸润的 NK 细胞中上调，特别是在具有衰竭表型和受损细胞毒性的 NK 细胞中。SIRT6 敲低显著增强了小鼠脾 NK 细胞的功能，表现在增殖加速、细胞毒性介质的产生增加以及体外和体内的杀伤活性更高。此外，将 SIRT6 敲低的 NK 细胞过继转移到 CRC 荷瘤小鼠中可有效抑制 CRC 进展。因此，SIRT6 的上调对于 CRC 中鼠 NK 细胞衰竭是必不可少的，因为它阻碍了鼠 NK 细胞的杀伤活性。人工 SIRT6 下调可以增强浸润 NK 细胞的功能，从而抑制小鼠 CRC 的进展。
