Jiang Bin, Zhou Hongjian, Xie Xingwang, Xia Tian, Ke Chao
The Department of Gastrointestinal, Hernia, and Abdominal Wall Surgery, Wuhan Third Hospital (Tongren Hospital of Wuhan University), Wuhan, Hubei Province, 430060, China.
Heliyon. 2024 Feb 7;10(4):e25721. doi: 10.1016/j.heliyon.2024.e25721. eCollection 2024 Feb 29.
Natural killer (NK) cells constitute an active and potent anti-tumor effector population against multiple malignancies. NK cells exploit tumoricidal machinery to restrain colorectal carcinoma (CRC) expansion and invasion. Nonetheless, it is becoming increasingly evident that functional exhaustion considerably compromises the potency of NK cells in patients with CRC. To elucidate the factors that impair NK cell function in the context of CRC, we determined the role of zinc finger protein 335 (ZFP335) in modulating NK cell activity in mouse CRC induced by azoxymethane and dextran sulfate sodium. ZFP335 was profoundly decreased in NK cells in mesenteric lymph nodes of CRC-bearing mice. ZFP335 was especially diminished in NK cells that were both phenotypically and functionally exhausted. Besides, effective ZFP335 knockdown markedly undermined NK cell proliferation, tumoricidal protein production, degranulation, and cytotoxic efficacy on malignant cells, strongly suggesting that ZFP335 reinforces NK cell function. Importantly, ZFP335 knockdown lowered the expression of Janus kinase 1 (JAK1) and Janus kinase 3 (JAK3), both of which play crucial roles in NK cell homeostasis and activation. Collectively, ZFP335 down-regulation is essential for NK cell exhaustion in mesenteric lymph nodes of mice with CRC. We discovered a new ZFP335-JAK1/3 signaling pathway that modulates NK cell exhaustion.
自然杀伤（NK）细胞构成了针对多种恶性肿瘤的活跃且强大的抗肿瘤效应细胞群体。NK细胞利用杀肿瘤机制来抑制结直肠癌（CRC）的扩展和侵袭。然而，越来越明显的是，功能耗竭极大地损害了CRC患者体内NK细胞的效能。为了阐明在CRC背景下损害NK细胞功能的因素，我们确定了锌指蛋白335（ZFP335）在调节由氧化偶氮甲烷和葡聚糖硫酸钠诱导的小鼠CRC中NK细胞活性方面的作用。在携带CRC的小鼠肠系膜淋巴结中的NK细胞中，ZFP335显著降低。在表型和功能上均耗竭的NK细胞中，ZFP335尤其减少。此外，有效的ZFP335敲低显著削弱了NK细胞的增殖、杀肿瘤蛋白产生、脱颗粒以及对恶性细胞的细胞毒性效力，强烈表明ZFP335增强了NK细胞功能。重要的是，ZFP335敲低降低了Janus激酶1（JAK1）和Janus激酶3（JAK3）的表达，这两者在NK细胞稳态和激活中都起着关键作用。总体而言，ZFP335下调对于CRC小鼠肠系膜淋巴结中的NK细胞耗竭至关重要。我们发现了一条调节NK细胞耗竭的新的ZFP335 - JAK1/3信号通路。
