封锁
癌症免疫疗法
癌症研究
效应器
免疫系统
免疫疗法
黑色素瘤
PD-L1
CD8型
抗体
免疫检查点
转化生长因子
阻断抗体
生物
癌症
受体
细胞毒性T细胞
肿瘤浸润淋巴细胞
免疫学
细胞生物学
体外
生物化学
遗传学
作者
Grégoire de Streel,Charlotte Bertrand,Nicolas Chalon,Stéphanie Liénart,Orian Bricard,Sara Stéphanie Lecomte,Julien Devreux,Mélanie Gaignage,Gitte De Boeck,Lore Mariën,Inge Van de Walle,Bas van der Woning,Michael Saunders,Hans de Haard,Elien Vermeersch,Wim Maes,Hans Deckmyn,Pierre G. Coulie,Nicolas van Baren,Sophie Lucas
标识
DOI:10.1038/s41467-020-17811-3
摘要
TGF-β1, β2 and β3 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-β inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-β1 production by Tregs with antibodies against GARP:TGF-β1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARP:TGF-β1/PD-1 blockade are immune-mediated, do not require FcγR-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-β1 in one third of human melanoma metastases. Our results suggest that anti-GARP:TGF-β1 mAbs, by selectively blocking a single TGF-β isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.
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