Oncostatin M Receptor-Targeted Antibodies Suppress STAT3 Signaling and Inhibit Ovarian Cancer Growth.
Oncostatin M Receptor-Targeted Antibodies Suppress STAT3 Signaling and Inhibit Ovarian Cancer Growth.
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DOI：
10.1158/0008-5472.can-21-0483
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发表时间：
2021-10-15
期刊：
影响因子：
11.2
通讯作者：
Chaluvally-Raghavan P
中科院分区：
文献类型：
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作者：
Geethadevi A;Nair A;Parashar D;Ku Z;Xiong W;Deng H;Li Y;George J;McAllister DM;Sun Y;Kadamberi IP;Gupta P;Dwinell MB;Bradley WH;Rader JS;Rui H;Schwabe RF;Zhang N;Pradeep S;An Z;Chaluvally-Raghavan P
虽然晚期卵巢癌患者最初可能对治疗有反应，但疾病复发很常见，近50%的患者生存期不超过5年，这表明迫切需要改进治疗方法。为了确定新的治疗靶点，我们对17例人卵巢癌标本进行了单细胞和核RNA-seq数据集分析，揭示了抑瘤素M受体（OSMR）在卵巢癌细胞中高度表达。相反，OSMR的配体抑瘤素M（OSM）在肿瘤相关巨噬细胞中高度表达，并促进癌细胞的增殖和转移。与肿瘤微环境中的其他细胞类型或正常卵巢组织样品相比，卵巢癌细胞系和其他患者样品也表现出OSMR水平升高。OSMR对卵巢癌细胞的增殖和迁移有重要作用。OSM与OSMR的结合导致OSMR-IL 6ST二聚化，这是产生延长的STAT 3活化的致癌信号传导线索所必需的。针对OSMR胞外结构域的人单克隆抗体克隆B14和B21在体外消除了OSM诱导的OSMR-IL 6ST异源二聚化，促进了OSMR的内化和降解，并有效地阻断了OSMR介导的信号传导。重要的是，这些抗体克隆通过OSMR和STAT 3激活抑制致癌信号传导，在体外和体内抑制卵巢癌细胞的生长。总的来说，本研究提供了抗OSMR抗体可以介导OSM诱导的OSMR-IL 6ST二聚化和致癌信号传导的破坏的原理证明，从而记录了人OSMR拮抗剂抗体用于卵巢癌免疫疗法的临床前治疗功效。这项研究揭示了OSMR通过激活STAT 3信号在促进卵巢癌细胞增殖和转移中的作用，并证明了基于抗体的OSMR靶向治疗卵巢癌的临床前疗效。
While 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 dataset 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 to 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 pre-clinical therapeutic efficacy of human OSMR antagonist antibodies for immunotherapy in ovarian cancer. 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.