Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: de Streel, Grégoire, Bertrand, Charlotte, Chalon, Nicolas, Liénart, Stéphanie, Bricard, Orian, Lecomte, Sara, Devreux, Julien, Gaignage, Mélanie, De Boeck, Gitte, Mariën, Lore, Van De Walle, Inge, van der Woning, Bas, Saunders, Michael, de Haard, Hans, Vermeersch, Elien, Maes, Wim, Deckmyn, Hans, Coulie, Pierre G., van Baren, Nicolas, Lucas, Sophie
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486376/
https://www.ncbi.nlm.nih.gov/pubmed/32917858
http://dx.doi.org/10.1038/s41467-020-17811-3
_version_ 1783581322612047872
author de Streel, Grégoire
Bertrand, Charlotte
Chalon, Nicolas
Liénart, Stéphanie
Bricard, Orian
Lecomte, Sara
Devreux, Julien
Gaignage, Mélanie
De Boeck, Gitte
Mariën, Lore
Van De Walle, Inge
van der Woning, Bas
Saunders, Michael
de Haard, Hans
Vermeersch, Elien
Maes, Wim
Deckmyn, Hans
Coulie, Pierre G.
van Baren, Nicolas
Lucas, Sophie
author_facet de Streel, Grégoire
Bertrand, Charlotte
Chalon, Nicolas
Liénart, Stéphanie
Bricard, Orian
Lecomte, Sara
Devreux, Julien
Gaignage, Mélanie
De Boeck, Gitte
Mariën, Lore
Van De Walle, Inge
van der Woning, Bas
Saunders, Michael
de Haard, Hans
Vermeersch, Elien
Maes, Wim
Deckmyn, Hans
Coulie, Pierre G.
van Baren, Nicolas
Lucas, Sophie
author_sort de Streel, Grégoire
collection PubMed
description 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.
format Online
Article
Text
id pubmed-7486376
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Nature Publishing Group UK
record_format MEDLINE/PubMed
spelling pubmed-74863762020-09-21 Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer de Streel, Grégoire Bertrand, Charlotte Chalon, Nicolas Liénart, Stéphanie Bricard, Orian Lecomte, Sara Devreux, Julien Gaignage, Mélanie De Boeck, Gitte Mariën, Lore Van De Walle, Inge van der Woning, Bas Saunders, Michael de Haard, Hans Vermeersch, Elien Maes, Wim Deckmyn, Hans Coulie, Pierre G. van Baren, Nicolas Lucas, Sophie Nat Commun Article 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. Nature Publishing Group UK 2020-09-11 /pmc/articles/PMC7486376/ /pubmed/32917858 http://dx.doi.org/10.1038/s41467-020-17811-3 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
de Streel, Grégoire
Bertrand, Charlotte
Chalon, Nicolas
Liénart, Stéphanie
Bricard, Orian
Lecomte, Sara
Devreux, Julien
Gaignage, Mélanie
De Boeck, Gitte
Mariën, Lore
Van De Walle, Inge
van der Woning, Bas
Saunders, Michael
de Haard, Hans
Vermeersch, Elien
Maes, Wim
Deckmyn, Hans
Coulie, Pierre G.
van Baren, Nicolas
Lucas, Sophie
Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer
title Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer
title_full Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer
title_fullStr Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer
title_full_unstemmed Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer
title_short Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer
title_sort selective inhibition of tgf-β1 produced by garp-expressing tregs overcomes resistance to pd-1/pd-l1 blockade in cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486376/
https://www.ncbi.nlm.nih.gov/pubmed/32917858
http://dx.doi.org/10.1038/s41467-020-17811-3
work_keys_str_mv AT destreelgregoire selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT bertrandcharlotte selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT chalonnicolas selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT lienartstephanie selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT bricardorian selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT lecomtesara selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT devreuxjulien selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT gaignagemelanie selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT deboeckgitte selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT marienlore selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT vandewalleinge selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT vanderwoningbas selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT saundersmichael selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT dehaardhans selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT vermeerschelien selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT maeswim selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT deckmynhans selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT couliepierreg selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT vanbarennicolas selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer
AT lucassophie selectiveinhibitionoftgfb1producedbygarpexpressingtregsovercomesresistancetopd1pdl1blockadeincancer