Mechanistic analysis of the antitumor efficacy of human natural killer cells against breast cancer cells
Mechanistic analysis of the antitumor efficacy of human natural killer cells against breast cancer cells
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DOI：
10.1007/s10549-011-1944-x
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发表时间：
2012-07-01
影响因子：
3.8
通讯作者：
Ohdan, Hideki
中科院分区：
文献类型：
--
作者：
Kajitani, Keiko;Tanaka, Yuka;Ohdan, Hideki
我们研究了人外周血（PB）和肝脏中自然杀伤细胞（NK）在控制乳腺癌中的作用。NK细胞在肝单个核细胞中的比例显著高于PB单个核细胞。在白介素-2 （IL-2）作用下，肝NK细胞诱导表达的肿瘤坏死因子相关凋亡诱导配体（TRAIL）水平高于PB NK细胞。IL-2刺激后，肝NK细胞对多种乳腺癌细胞系（MDA-MB231、MDA-MB453、MDA-MB468和MCF-7）的细胞毒性高于PB NK细胞。抗her2单克隆抗体（mAb）可促进两种NK细胞对表达her2的细胞系的细胞毒性。所有乳腺癌细胞系均高度表达诱导死亡的TRAIL受体、死亡受体4，但不表达死亡抑制受体（DcR1和DcR2）。抗TRAIL单抗可部分抑制PB和肝脏NK细胞诱导的细胞毒性，而抗TRAIL单抗与康纳霉素A联用可更深刻地抑制PB和肝NK细胞诱导的细胞毒性，表明TRAIL和穿孔素参与其中。il -2刺激的肝脏和PB NK细胞表达上调，CXCR3与乳腺癌细胞分泌的趋化因子CXCL9、CXCL10和CXCL11结合。我们还发现ifn - γ促进乳腺癌细胞中CXCL10的产生。本研究结果表明NK细胞分泌的ifn - γ可能促进乳腺癌细胞产生CXCL10，进而加速表达cxcr3的NK细胞向肿瘤部位的迁移。这些发现表明，通过激活内源性PB和肝脏NK细胞或过继性转移体外活化的自体NK细胞来治疗的可能性。
We investigated the role of human natural killer (NK) cells in the peripheral blood (PB) and liver in controlling breast cancer. The proportion of NK cells among liver mononuclear cells was significantly higher than among PB mononuclear cells. Liver NK cells inductively expressed higher levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) than PB NK cells in response to interleukin-2 (IL-2). Liver NK cells displayed higher cytotoxicity against various breast cancer cell lines (MDA-MB231, MDA-MB453, MDA-MB468, and MCF-7) after IL-2 stimulation than did PB NK cells. Anti-HER2 monoclonal antibody (mAb) promoted the cytotoxicity of both the types of NK cells toward HER2-expressing cell lines. All breast cancer cell lines highly expressed death-inducing TRAIL receptors, death receptor 4, but did not express death-inhibitory receptors (DcR1 and DcR2). Both PB and liver NK cell-induced cytotoxicity was inhibited partially by anti-TRAIL mAb and more profoundly by the combination of anti-TRAIL mAb and concanamycin A, indicating that TRAIL and perforin are involved. IL-2-stimulated liver and PB NK cells exhibited upregulated expression of CXCR3, which bind to the chemokines CXCL9, CXCL10, and CXCL11 secreted by breast cancer cells. We also found that IFN-gamma promoted the production of CXCL10 from breast cancer cells. The results of this study show that IFN-gamma secreted from NK cells likely promotes the production of CXCL10 from breast cancer cells, which in turn accelerates the migration of CXCR3-expressing NK cells into the tumor site. These findings suggest the possibility of a therapeutic approach by either activation of endogenous PB and liver NK cells or adoptive transfer of in vitro-activated autologous NK cells.