N-cadherin protects oral cancer cells from NK cell killing in the circulation by inducing NK cell functional exhaustion via the KLRG1 receptor.
N-cadherin protects oral cancer cells from NK cell killing in the circulation by inducing NK cell functional exhaustion via the KLRG1 receptor.
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n -钙粘蛋白通过KLRG1受体诱导NK细胞功能衰竭，保护口腔癌细胞免受循环中NK细胞的杀伤。
DOI：
10.1136/jitc-2022-005061
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发表时间：
2022-09
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
循环肿瘤细胞（CTC）可以在循环中存活，并通过自我接种过程返回原发性肿瘤。然而，CTC逃避自然杀伤（NK）细胞介导的免疫监视的潜在机制仍不清楚。使用改良的对侧接种模型分离和表征自接种肿瘤细胞。在亲本细胞和自接种细胞之间进行转录谱的比较。通过体外实验证明了自接种肿瘤细胞逃离NK细胞的分子机制，并在CTC模拟体内模型中得到验证。采用免疫组化方法检测24例口腔癌患者原发灶和复发灶中CTCs免疫逃逸关键蛋白的表达水平。自接种细胞显示出对NK细胞介导的裂解的抗性，并且比其亲本细胞具有更高的肿瘤接种能力。在自接种细胞中发现CDH 2基因及其蛋白产物N-钙粘蛋白的表达水平升高。NK细胞分泌细胞因子，流体剪切力通过促进A解整合素和金属蛋白酶10（ADAM 10）的翻译或将前体ADAM 10转化为成熟形式促进N-钙粘蛋白的释放。可溶性N-钙粘蛋白通过与杀伤细胞凝集素样受体亚家族G成员1（KLRG 1）受体相互作用触发NK细胞功能衰竭，从而保护肿瘤细胞免受循环中NK细胞杀伤。体内实验结果表明，N-cadherin的过表达促进了肿瘤的自我种植，促进了CTC的存活。与原发性肿瘤相比，匹配的复发肿瘤组织中N-钙粘蛋白表达显着增加。总之，我们的研究结果说明了CTC逃避NK细胞介导的免疫监视的未知机制，并表明靶向N-钙粘蛋白是防止CTC归巢至原发性肿瘤的有效策略。
Circulating tumor cells (CTCs) can survive in the circulation and return to primary tumors through a self-seeding process. However, the mechanisms underlying CTCs escape from natural killer (NK) cell-mediated immune surveillance remain unclear. Self-seeded tumor cells were isolated and characterized using a modified contralateral seeding model. A comparison of transcriptional profiles was performed between the parental cells and self-seeded cells. The molecular mechanism of self-seeded tumor cells escaping from NK cell was demonstrated through in vitro experiments and verified in a CTC-mimicking in vivo model. Then, the expression level of key protein mediating CTCs immune escape was detected in 24 paired primary and recurrent tumor samples of patients with oral cancer by the immunohistochemical method. Self-seeded cells displayed resistance to NK cell-mediated lysis and a higher tumor seeding ability than their parental cells. Elevated expression levels of the CDH2 gene and its protein product, N-cadherin were found in self-seeded cells. NK cells secreted cytokines, and fluid shear stress facilitated N-cadherin release by promoting A disintegrin and metalloprotease 10 (ADAM10) translation or converting the precursor ADAM10 to the mature form. Soluble N-cadherin triggered NK cell functional exhaustion by interacting with the killer cell lectin-like receptor subfamily G member 1 (KLRG1) receptor and therefore protected tumor cells from NK cell killing in the circulation. In vivo experimental results showed that overexpression of N-cadherin promoted tumor self-seeding and facilitated the survival of CTCs. Compared with primary tumors, N-cadherin expression was significantly increased in matched recurrent tumor tissues. Together, our findings illustrate an unknown mechanism by which CTCs evaded NK cell-mediated immune surveillance, and indicate that targeting N-cadherin is an effective strategy to prevent CTCs from homing to primary tumor.
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影响因子：
32.4
作者：
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