Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity

被引：346

作者：

de Andrade, Lucas Ferrari ^{[1
,2
]}

Tay, Rong En ^{[1
,2
]}

Pan, Deng ^{[1
,2
]}

Luoma, Adrienne M. ^{[1
,2
]}

Ito, Yoshinaga ^{[1
,2
]}

Badrinath, Soumya ^{[1
,2
]}

Tsoucas, Daphne ^{[3
]}

Franz, Bettina ^{[1
,2
]}

May, Kenneth F., Jr. ^{[4
]}

Harvey, Christopher J. ^{[1
]}

Kobold, Sebastian ^{[1
]}

Pyrdol, Jason W. ^{[1
]}

Yoon, Charles ^{[4
,5
]}

Yuan, Guo-Cheng ^{[3
]}

Hodi, F. Stephen ^{[4
]}

Dranoff, Glenn ^{[4
,6
]}

Wucherpfennig, Kai W. ^{[1
,2
]}

机构：

[1] Dana Farber Canc Inst, Dept Canc Immunol & Virol, 450 Brookline Ave, Boston, MA 02215 USA

[2] Harvard Med Sch, 25 Shattuck St, Boston, MA 02115 USA

[3] Dana Farber Canc Inst, Dept Biostat & Computat Biol, 450 Brookline Ave, Boston, MA 02215 USA

[4] Dana Farber Canc Inst, Dept Med Oncol, 450 Brookline Ave, Boston, MA 02215 USA

[5] Brigham & Womens Hosp, Dept Surg, 75 Francis St, Boston, MA 02115 USA

[6] Novartis Inst BioMed Res, 250 Massachusetts Ave, Cambridge, MA 02139 USA

来源：

SCIENCE | 2018年 / 359卷 / 6383期

关键词：

I-RELATED CHAIN; NKG2D RECEPTOR; T-CELLS; CUTTING EDGE; LIGANDS; EXPRESSION; ACTIVATION; CANCER; CYTOTOXICITY; MOLECULES;

D O I：

10.1126/science.aao0505

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 alpha 3 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.

引用

收藏

页码：1537 / +

页数：6

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