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

Grégoire de Streel, Charlotte Bertrand, Nicolas Chalon, Stéphanie Liénart, Orian Bricard, Sara 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 and Sophie Lucas ()
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Grégoire de Streel: Université catholique de Louvain
Charlotte Bertrand: Université catholique de Louvain
Nicolas Chalon: Université catholique de Louvain
Stéphanie Liénart: Université catholique de Louvain
Orian Bricard: Université catholique de Louvain
Sara Lecomte: Université catholique de Louvain
Julien Devreux: Université catholique de Louvain
Mélanie Gaignage: Université catholique de Louvain
Gitte De Boeck: argenx
Lore Mariën: argenx
Inge Van De Walle: argenx
Bas van der Woning: argenx
Michael Saunders: argenx
Hans de Haard: argenx
Elien Vermeersch: Laboratory for Thrombosis Research, IRF Life Sciences
Wim Maes: Laboratory for Thrombosis Research, IRF Life Sciences
Hans Deckmyn: Laboratory for Thrombosis Research, IRF Life Sciences
Pierre G. Coulie: Université catholique de Louvain
Nicolas van Baren: Université catholique de Louvain
Sophie Lucas: Université catholique de Louvain

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-17811-3

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DOI: 10.1038/s41467-020-17811-3

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