High-grade serous ovarian tumor cells modulate NK cell function to create an immune-tolerant microenvironment

被引：44

作者：

Gonzalez, Veronica D. ^{[1
,8
]}

Huang, Ying-Wen ^{[2
]}

Delgado-Gonzalez, Antonio ^{[2
]}

Chen, Shih-Yu ^{[1
,9
]}

Donoso, Kenyi ^{[2
]}

Sachs, Karen ^{[3
]}

Gentles, Andrew J. ^{[4
,5
]}

Allard, Grace M. ^{[6
]}

Kolahi, Kevin S. ^{[6
]}

Howitt, Brooke E. ^{[5
,6
]}

Porpiglia, Ermelinda ^{[1
]}

Fantl, Wendy J. ^{[1
,5
,7
]}

机构：

[1] Stanford Univ, Dept Microbiol & Immunol, Baxter Lab Stem Cell Biol, Sch Med, Stanford, CA 94305 USA

[2] Stanford Univ, Dept Urol, Sch Med, Stanford, CA 94305 USA

[3] Next Generat Analyt, Palo Alto, CA 94301 USA

[4] Stanford Univ, Sch Med, Dept Med,Biomed Data Sci, Quantitat Sci Unit,Biomed Informat, Stanford, CA 94305 USA

[5] Stanford Univ, Stanford Canc Inst, Sch Med, Stanford, CA 94305 USA

[6] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA

[7] Stanford Univ, Dept Obstet & Gynecol, Sch Med, Stanford, CA 94305 USA

[8] 10X Genom, Pleasanton, CA 94588 USA

[9] Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan

来源：

CELL REPORTS | 2021年 / 36卷 / 09期

关键词：

NATURAL-KILLER-CELLS; I-RELATED CHAIN; T-CELLS; CANCER-IMMUNOTHERAPY; MEMBRANE-FRAGMENTS; MASS CYTOMETRY; TARGET-CELLS; NKG2D; TROGOCYTOSIS; CYTOKINE;

D O I：

10.1016/j.celrep.2021.109632

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Tubo-ovarian high-grade serous carcinoma (HGSC) is unresponsive to immune checkpoint blockade despite significant frequencies of exhausted T cells. Here we apply mass cytometry and uncover decidual-like natural killer (dl-NK) cell subpopulations (CD56+CD9+CXCR3+KIR+CD3-CD16-) in newly diagnosed HGSC samples that correlate with both tumor and transitioning epithelial-mesenchymal cell abundance. We show different combinatorial expression patterns of ligands for activating and inhibitory NK receptors within three HGSC tumor compartments: epithelial (E), transitioning epithelial-mesenchymal (EV), and mesenchymal (vimentin expressing [V]), with a more inhibitory ligand phenotype in V cells. In cocultures, NK-92 natural killer cells acquire CD9 from HGSC tumor cells by trogocytosis, resulting in reduced anti-tumor cytokine production and cytotoxicity. Cytotoxicity in these cocultures is restored with a CD9-blocking antibody or CD9 CRISPR knockout, thereby identifying mechanisms of immune suppression in HGSC. CD9 is widely expressed in HGSC tumors and so represents an important new therapeutic target with immediate relevance for NK immunotherapy.

引用

页数：24

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