Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer

被引：112

作者：

de Streel, Gregoire ^{[1
]}

Bertrand, Charlotte ^{[1
]}

Chalon, Nicolas ^{[1
]}

Lienart, Stephanie ^{[1
]}

Bricard, Orian ^{[1
]}

Lecomte, Sara ^{[1
]}

Devreux, Julien ^{[1
]}

Gaignage, Melanie ^{[1
]}

De Boeck, Gitte ^{[2
]}

Marien, Lore ^{[2
]}

Van de Walle, Inge ^{[2
]}

van der Woning, Bas ^{[2
]}

Saunders, Michael ^{[2
]}

de Haard, Hans ^{[2
]}

Vermeersch, Elien ^{[3
]}

Maes, Wim ^{[3
]}

Deckmyn, Hans ^{[3
]}

Coulie, Pierre G. ^{[1
]}

van Baren, Nicolas ^{[1
]}

Lucas, Sophie ^{[1
]}

机构：

[1] Catholic Univ Louvain, de Duve Inst, B-1200 Brussels, Belgium

[2] Argenx, B-9052 Zwijnaarde, Belgium

[3] Katholieke Univ Leuven, IRF Life Sci, Lab Thrombosis Res, Campus Kulak Kortrijk, B-8500 Kortrijk, Belgium

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

欧洲研究理事会;

关键词：

REGULATORY T-CELLS; LATENT TGF-BETA; ANTITUMOR-ACTIVITY; PD-1; BLOCKADE; ANTIBODIES; GENE; RECEPTOR;

D O I：

10.1038/s41467-020-17811-3

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：

TGF-beta 1, beta 2 and beta 3 bind a common receptor to exert vastly diverse effects in cancer, supporting either tumor progression by favoring metastases and inhibiting anti-tumor immunity, or tumor suppression by inhibiting malignant cell proliferation. Global TGF-beta inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-beta 1 production by Tregs with antibodies against GARP:TGF-beta 1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-beta 1/PD-1 blockade are immune-mediated, do not require Fc gamma R-dependent functions and increase effector functions of anti-tumor CD8(+) T cells without augmenting immune cell infiltration or depleting Tregs within tumors. We find GARP-expressing Tregs and evidence that they produce TGF-beta 1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-beta 1 mAbs, by selectively blocking a single TGF-beta isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.

引用

页数：15

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