Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity
Human breast cancer cells enhance self tolerance by promoting evasion from NK cell antitumor immunity
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DOI：
10.1172/jci45816
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发表时间：
2011-09-01
影响因子：
15.9
通讯作者：
Olive, Daniel
中科院分区：
文献类型：
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作者：
Mamessier, Emilie;Sylvain, Aude;Olive, Daniel
NK细胞是抗肿瘤免疫应答的主要成分，并参与控制动物模型中的肿瘤进展和转移。在这里，我们发现这些细胞的功能障碍伴随着人类乳腺肿瘤的进展。我们对非侵袭性和侵袭性乳腺癌患者的人外周血NK（p-NK）细胞和恶性乳腺肿瘤浸润性NK（Ti-NK）细胞进行了表征。从健康供体的外周血和正常乳腺组织中分离的NK细胞用作对照。随着疾病进展，我们发现活化NK细胞受体（如NKp 30、NKG 2D、DNAM-1和CD 16）的表达降低，而抑制性受体（如NKG 2A）的表达增加，这与NK细胞功能降低相关，最显著的是细胞毒性。重要的是，Ti-NK细胞比p-NK细胞对它们的细胞毒性潜力具有更明显的损害。我们还确定了几种基质衍生因子，包括TGF-β 1，参与肿瘤诱导的正常NK细胞功能降低。因此，我们的数据表明，乳腺肿瘤的进展涉及NK细胞功能障碍，乳腺肿瘤模拟其环境，以逃避NK细胞抗肿瘤免疫。这突出了开发能够恢复NK细胞细胞毒性以限制/防止肿瘤逃避抗肿瘤免疫的未来疗法的重要性。
NK cells are a major component of the antitumor immune response and are involved in controlling tumor progression and metastases in animal models. Here, we show that dysfunction of these cells accompanies human breast tumor progression. We characterized human peripheral blood NK (p-NK) cells and malignant mammary tumor-infiltrating NK (Ti-NK) cells from patients with noninvasive and invasive breast cancers. NK cells isolated from the peripheral blood of healthy donors and normal breast tissue were used as controls. With disease progression, we found that expression of activating NK cell receptors (such as NKp30, NKG2D, DNAM-1, and CD 16) decreased while expression of inhibitory receptors (such as NKG2A) increased and that this correlated with decreased NK cell function, most notably cytotoxicity. Importantly, Ti-NK cells had more pronounced impairment of their cytotoxic potential than p-NK cells. We also identified several stroma-derived factors, including TGF-beta 1, involved in tumor-induced reduction of normal NK cell function. Our data therefore show that breast tumor progression involves NK cell dysfunction and that breast tumors model their environment to evade NK cell antitumor immunity. This highlights the importance of developing future therapies able to restore NK cell cytotoxicity to limit/prevent tumor escape from antitumor immunity.