Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity.
Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity.
复制标题
DOI：
10.1126/science.aao0505
复制
发表时间：
2018-03-30
期刊：
影响因子：
--
通讯作者：
Wucherpfennig KW
中科院分区：
文献类型：
--
作者：
Ferrari de Andrade L;Tay RE;Pan D;Luoma AM;Ito Y;Badrinath S;Tsoucas D;Franz B;May KF Jr;Harvey CJ;Kobold S;Pyrdol JW;Yoon C;Yuan GC;Hodi FS;Dranoff G;Wucherpfennig KW
由于细胞应激，许多人类癌症会表达MICA和MICB，并且它们可通过激活自然杀伤细胞2D组（NKG2D）受体标记细胞，使其被细胞毒性淋巴细胞清除。然而，肿瘤通过MICA和MICB蛋白的蛋白水解性脱落来逃避这种免疫识别途径。我们合理设计了针对MICA α3结构域（即蛋白水解性脱落位点）的抗体，发现这些抗体可阻止人类癌细胞表面MICA和MICB的缺失。这些抗体在多种具有完全免疫能力的小鼠模型中抑制了肿瘤生长，并在人源化小鼠模型中减少了人类黑色素瘤的转移。抗肿瘤免疫主要由自然杀伤（NK）细胞通过激活NKG2D和CD16 Fc受体来介导。这种方法可防止人类癌症丢失重要的免疫刺激配体，并重新激活抗肿瘤免疫。
MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.
登录
查看更多内容
影响因子：
4.4
作者：
Lee, JC;Lee, KM;Heo, DS
通讯作者：
Heo, DS
影响因子：
15.9
作者：
Liu, Gang;Lu, Shengjun;Wu, Jennifer D.
通讯作者：
Wu, Jennifer D.
影响因子：
6.4
作者：
Holdenrieder, S;Stieber, P;Salih, HR
通讯作者：
Salih, HR
影响因子：
56.9
作者：
Bauer, S;Groh, V;Spies, T
通讯作者：
Spies, T
影响因子：
4.3
作者：
Izar, Benjamin;Joyce, Cailin E.;Yoon, Charles H.
通讯作者：
Yoon, Charles H.