Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models

Abstract

Blockade of TGF-β signaling with novel synthetic antibodies limits immune exclusion and improves chemotherapy response in metastatic ovarian cancer models, OncoImmunology, 8:2, e1539613, ABSTRACT Epithelial ovarian cancer (EOC) is a leading cause of cancer-related death in women. EOC is often diagnosed at late stages, with peritoneal metastases and ascites production. Current surgery and platinum-based chemotherapy regimes fail to prevent recurrence in most patients. High levels of Transforming growth factor-β (TGF-β) within ascites has been linked to poor prognosis. TGF-β signaling promotes epithelial-mesenchymal transition (EMT) in EOC tumor cells, and immune suppression within the tumor microenvironment, with both contributing to chemotherapy resistance and metastasis. The goal of this study was to develop specific synthetic inhibitory antibodies to the Type II TGF-β receptor (TGFBR2), and test these antibodies in EOC cell and tumor models. Following screening of a phage-displayed synthetic antigen-binding fragment (Fab) library with the extracellular domain of TGFBR2, we identified a lead inhibitory Fab that suppressed TGF-β signaling in mouse and human EOC cell lines. Affinity maturation of the lead inhibitory Fab resulted in several derivative Fabs with increased affinity for TGFBR2 and efficacy as suppressors of TGF-β signaling, EMT and EOC cell invasion. In EOC xenograft and syngeneic tumor models, blockade of TGFBR2 with our lead antibodies led to improved chemotherapy response. This correlated with reversal of EMT and immune exclusion in these tumor models with TGFBR2 blockade. Together, these results describe new inhibitors of the TGF-β pathway that improve antitumor immunity, and response to chemotherapy in preclinical EOC models. ARTICLE HISTORY

A TGF-β associated genetic score to define prognosis and platinum sensitivity in advanced epithelial ovarian cancer

“…Our TGF-b pathway score was able to identify patients with different risk of platinum resistance. This is in line with previous studies showing that the TGF-b signalling participates in epithelial-mesenchymal transition (EMT) in EOC tumour cells, and in the creation of an immunosuppressive microenvironment, phenomena contributing to chemotherapy resistance [31]. Moreover, some studies have reported the involvement of TGF-b signalling in platinum resistance, both in ovarian cancer cell lines [31] and patients [32].…”

The Role of Epithelial-to-Mesenchymal Plasticity in Ovarian Cancer Progression and Therapy Resistance

“…This in turn led to the development of HGS ovarian cancer precursor lesions, so-called secretory cell outgrowths (SCOUTS) and serous tubal intraepithelial carcinomas (STIC) [30]. This EMT and subsequent emergence of HGS ovarian cancer precursor lesions could be initiated by various stimuli, including TGFβ, a potent EMT-inducer present in the follicular fluid, which is released during ovulation [30,38] (Figure 1).…”

“…One example is the potent TGFβ inhibitor, SB-431542, which increased carboplatin sensitivity [61]. Likewise, synthetic inhibitory antibodies to the type II TGF-β receptor (TGFBR2), reversed EMT and improved the response to carboplatin and anti-tumor immunity in vivo (fewer Tregs and more cytotoxic immune cells in the tumors) [38]. Furthermore, treatment with siRNA targeting TWIST increased platinum sensitivity in vivo.…”

Review: Targeting the Transforming Growth Factor-Beta Pathway in Ovarian Cancer

“…Newsted et al identified a lead inhibitory antigen-binding fragment (Fab) via screening of a synthetic library with TβRII. Suppression with this lead Fab resulted in the reversal of the EMT and tumor invasion and an improved response to chemotherapy in EOC xenograft and syngeneic models [115]. Genzyme (1D11) is a neutralizing monoclonal antibody active against all three isoforms of TGF-β and was shown to reduce tumor dissemination in breast cancer [116,117,118].…”