Oncostatin M Receptor–Targeted Antibodies Suppress STAT3 Signaling and Inhibit Ovarian Cancer Growth

Abstract

Although patients with advanced ovarian cancer may respond initially to treatment, disease relapse is common, and nearly 50% of patients do not survive beyond five years, indicating an urgent need for improved therapies. To identify new therapeutic targets, we performed single-cell and nuclear RNA-seq data set analyses on 17 human ovarian cancer specimens, revealing the oncostatin M receptor (OSMR) as highly expressed in ovarian cancer cells. Conversely, oncostatin M (OSM), the ligand of OSMR, was highly expressed by tumor-associated macrophages and promoted proliferation and metastasis in cancer cells. Ovarian cancer cell lines and additional patient samples also exhibited elevated levels of OSMR when compared with other cell types in the tumor microenvironment or to normal ovarian tissue samples. OSMR was found to be important for ovarian cancer cell proliferation and migration. Binding of OSM to OSMR caused OSMR–IL6ST dimerization, which is required to produce oncogenic signaling cues for prolonged STAT3 activation. Human monoclonal antibody clones B14 and B21 directed to the extracellular domain of OSMR abrogated OSM-induced OSMR–IL6ST heterodimerization, promoted the internalization and degradation of OSMR, and effectively blocked OSMR-mediated signaling in vitro. Importantly, these antibody clones inhibited the growth of ovarian cancer cells in vitro and in vivo by suppressing oncogenic signaling through OSMR and STAT3 activation. Collectively, this study provides a proof of principle that anti-OSMR antibody can mediate disruption of OSM-induced OSMR–IL6ST dimerization and oncogenic signaling, thus documenting the preclinical therapeutic efficacy of human OSMR antagonist antibodies for immunotherapy in ovarian cancer. Significance: This study uncovers a role for OSMR in promoting ovarian cancer cell proliferation and metastasis by activating STAT3 signaling and demonstrates the preclinical efficacy of antibody-based OSMR targeting for ovarian cancer treatment.

Patient-Derived Ovarian Cancer Spheroids Rely on PI3K-AKT Signaling Addiction for Cancer Stemness and Chemoresistance

“…Immunoblotting was performed as described earlier with some modification [ 16 , 17 , 18 ]. Briefly, whole-cell lysates were prepared from 2D or 3D cultures.…”

Attenuated expression of SNF5 facilitates progression of bladder cancer via STAT3 activation

“…IHC was performed as previously described [ 17 ]. Briefly, tissues were fixed, paraffin-embedded, and sliced into 5 μm thick sections.…”

Molecular profile of pure squamous cell carcinoma of the bladder identifies major roles for OSMR and YAP signalling

“…Gain or amplification of 5p and increased expression of OSMR, its ligand OSM, and binding partner IL31RA signalling via which is known to upregulate STAT3 suggest that this signalling pathway acts as a critical oncogenic driver. Inhibition of the pathway in cervical SCC and ovarian cancer models using antibodies to OSMR has shown significant inhibition of STAT3 activation [ 36 , 91 ]. Thus, we suggest that inhibition of OSMR or OSM might be effective in bladder SCC.…”