CD16+ NKG2Ahigh Natural Killer Cells Infiltrate Breast Cancer-Draining Lymph Nodes
CD16+ NKG2Ahigh Natural Killer Cells Infiltrate Breast Cancer-Draining Lymph Nodes
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DOI：
10.1158/2326-6066.cir-18-0085
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发表时间：
2019-02-01
影响因子：
10.1
通讯作者：
Caignard, Anne
中科院分区：
文献类型：
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作者：
Frazao, Alexandra;Messaoudene, Meriem;Caignard, Anne
肿瘤引流淋巴结（TD-LN）是乳腺癌转移的首选部位。对浸润TD-LN [包括来自乳腺癌患者的非侵袭性（NI）或转移性（M）-LN]的自然杀伤（NK）细胞和来自健康供体（HD）-LN的NK细胞进行表征，并通过流式细胞术分析其表型。低百分比的肿瘤细胞侵入M-LN，并且这些细胞表达ULBP 2和HLA I类分子。尽管来自配对NI和M-LN的NK细胞相似，但与HD-LN NK细胞相比，它们表达不同的标志物。与HD-LN相比，TD-LN NK细胞表达激活性DNAM-1、NKG 2C和抑制性NKG 2A受体，并表现出CXCR 3表达升高。在IIIA期乳腺癌患者中，CD 16、NKG 2A和NKp 46表达增加。TD-LN中含有大量活化的CD 56 brightCD 16 thorn NK细胞，并高表达NKG 2A。我们还表明，LN NK细胞的一个子集表达PD-1，其表达与NKp 30和NKG 2C表达相关。LN NK细胞活化状态通过对乳腺癌细胞的脱粒潜力和溶解能力来评估。来自TD-LN的NK细胞在与乳腺癌细胞系共培养后脱颗粒。细胞因子活化的TD-LN NK细胞对乳腺癌细胞系的溶解作用大于HD-LN NK细胞，并且优先溶解HLA I类低MCF-7乳腺癌细胞系。因此，来自乳腺癌患者的TD-LN含有活化的溶解性NK细胞。浸润乳腺癌引流淋巴结的NK细胞表达抑制性受体NKG 2A和检查点PD-1，支持其作为使用抗NKG 2A和/或抗PD-1的免疫治疗靶点的潜力。
Tumor-draining lymph nodes (TD-LNs) are the first site of metastasis of breast cancer. Natural killer (NK) cells that infiltrate TD-LNs [including noninvaded (NI) or metastatic (M)-LNs from breast cancer patients] and NK cells from healthy donor (HD)-LNs were characterized, and their phenotype analyzed by flow cytometry. Low percentages of tumor cells invaded M-LNs, and these cells expressed ULBP2 and HLA class I molecules. Although NK cells from paired NI and M-LNs were similar, they expressed different markers compared with HD-LN NK cells. Compared with HD-LNs, TD-LN NK cells expressed activating DNAM-1, NKG2C and inhibitory NKG2A receptors, and exhibited elevated CXCR3 expression. CD16, NKG2A, and NKp46 expression were shown to be increased in stage IIIA breast cancer patients. TD-LNs contained a large proportion of activated CD56brightCD16 thorn NK cells with high expression of NKG2A. We also showed that a subset of LN NK cells expressed PD-1, expression of which was correlated with NKp30 and NKG2C expression. LN NK cell activation status was evaluated by degranulation potential and lytic capacity toward breast cancer cells. NK cells from TD-LNs degranulated after coculture with breast cancer cell lines. Cytokine-activated TD-LN NK cells exerted greater lysis of breast cancer cell lines than HD-LN NK cells and preferentially lysed the HLA class I-low MCF-7 breast cancer cell line. TD-LNs from breast cancer patients, thus, contained activated lytic NK cells. The expression of inhibitory receptor NKG2A and checkpoint PD-1 by NK cells infiltrating breast cancer-draining LNs supports their potential as targets for immunotherapies using anti-NKG2A and/or anti-PD-1.