Selective Inhibition Of Tgf-Beta 1 Produced By Garp-Expressing Tregs Overcomes Resistance To Pd-1/Pd-L1 Blockade In Cancer

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.