Selective inhibition of TGF-ß1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer.
Nat Commun
; 11(1): 4545, 2020 09 11.
Article
in En
| MEDLINE
| ID: mdl-32917858
ABSTRACT
TGF-ß1, ß2 and ß3 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-ß inhibition thus bears the risk of undesired tumor-promoting effects. We show that selective blockade of TGF-ß1 production by Tregs with antibodies against GARPTGF-ß1 complexes induces regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. Effects of combined GARPTGF-ß1/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-ß1 in one third of human melanoma metastases. Our results suggest that anti-GARPTGF-ß1 mAbs, by selectively blocking a single TGF-ß isoform emanating from a restricted cellular source exerting tumor-promoting activity, may overcome resistance to PD-1/PD-L1 blockade in patients with cancer.
Full text:
1
Database:
MEDLINE
Main subject:
Drug Resistance, Neoplasm
/
Transforming Growth Factor beta1
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Antineoplastic Agents, Immunological
/
Membrane Proteins
/
Neoplasms
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Year:
2020
Type:
Article