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

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.

Therapeutic targeting of TGF-β in cancer: hacking a master switch of immune suppression

“…Importantly, no (cardio)toxicity was observed, which could be due to the specific targeting of the TGF-β1 isoform; TGF-β2 and TGF-β3 have been shown to have important functions in the cardiovascular system in humans [131][132][133][134]. Also, an antibody that targets Garp and Tgf-β1 in a colon carcinoma mouse model was found to increase the anti-tumour efficacy of anti-Pd-1 therapy [135]. This observation was explained by immune-related effects that included increased activation of CD8 + T cells and inhibition of TGF-β-mediated, Treg immune suppressive activity [135].…”

“…Also, an antibody that targets Garp and Tgf-β1 in a colon carcinoma mouse model was found to increase the anti-tumour efficacy of anti-Pd-1 therapy [135]. This observation was explained by immune-related effects that included increased activation of CD8 + T cells and inhibition of TGF-β-mediated, Treg immune suppressive activity [135]. Also, thrombin was found to mediate the release of active Tgf-β by cleaving Garp from platelets, resulting in systemic activation of latent Tgf-β in tumour bearing mice.…”

Targeting TGFβ signal transduction for cancer therapy

“…278,298 A recent study discovered that an anti-GARP:TGFβ1 mAb (ABBV151), which selectively blocks TGFβ1 production by T reg cells, can induce the regression of anti-PD-1 immunotherapy-resistant tumors in a mouse cancer model. 299,300 The phase 1 clinical trial of an anti-GARP:TGFβ1 mAb (ABBV151) as monotherapy and in combination with the anti-PD1 mAb budigalimab (ABBV-181) were recently initiated for the evaluation of their safety and tolerability for patients with advanced solid tumors (NCT03821935).…”

TGFβ signaling networks in ovarian cancer progression and plasticity

“…The findings from the OI trials could have beneficial side effects for the management of ovarian cancer patients as well who are mostly menopausal and over time suffer significant bone mass loss [ 258 ].Trabedersen (AP12009 or OT-101) has also emerged as an alternative strategy, which is an antisense approach targeting TGFβ specifically and has shown significant promise in pre-clinical ovarian cancer models [ 259 ]. Another approach to block TGFβ at the ligand level is to block activation using anti-integrin approaches [ 260 ] and anti-GARP (ABBV151) approaches [ 261 ]. GARP is specifically required for TGFβ activation in regulatory T cells (Tregs) and platelets and ABBV151 is currently in clinical trials (Table 2 ) in combination with immune checkpoint inhibitors (ICI).…”