白介素-27介导卵巢癌免疫调节性抗体治疗抵抗的机制研究

The prognosis of patients with advanced epithelial ovarian cancer is dismal due to frequent cancer recurrence, which urgently calls for the novel therapeutic modalities. Immunomodulatory monoclonal antibody (imAb) is a novel class of protein drug targeting key co-signaling molecules on T cells, which has demonstrated an extremely exciting therapeutic efficacy in multiple types of solid tumor via enhancement of endogenous antitumor immunity. Using mouse ID8 syngeneic orthotopic epithelial ovarian cancer model, we has shown that treatments with suitable combinations of imAb effectively led to the regression of early-stage tumors, however, it was not curative for advanced tumors. We found that IL-27 expression was significantly upregulated in tumor-associated lymphocytes via analysis of the expression of 40 immune-associated genes in these cells by high-throughput PCR array, and blockade of IL-27 by IL-27-specific neutralizing antibody rescued the antitumor efficacy of combined imAb in vivo. These data strongly suggest an involvement of IL-27 in the resistance of advanced ovarian cancer to imAb treatment. In this study, we will further validate the role of IL-27 in the resistance of advanced ovarian cancer to imAb treatment by exploiting antiobdy blockade experiments; define the cells responsible for IL-27 production and molecular mechanisms for IL-27 induction, and finally elucidate the immune effector mechanisms by which IL-27 mediated resistance to imAb treatment. The study should reveal a novel mechanism of imAb resistance and provide a strong rationale for optimizing imAb application and increasing their efficacy in clinic.

晚期卵巢癌极易复发，病人预后不佳，急需新的治疗手段。免疫调节性抗体（imAb）是一类靶向T细胞表面共信号分子的具有免疫刺激功能的蛋白类药物，能够有效提高机体抗肿瘤免疫应答，在多种实体瘤中显示良好治疗前景。利用ID8小鼠原位表皮卵巢癌模型，我们发现联合imAb治疗能够有效治愈早期卵巢癌，但对晚期肿瘤疗效不佳。初步分析治疗抵抗机制发现，IL-27在治疗中后期肿瘤相关淋巴细胞中明显升高，体内阻断IL-27显著增强了imAb的抗肿瘤效应，提示IL-27介导imAb治疗抵抗。本研究中我们拟利用IL-27及IL-27受体特异阻断抗体进一步明确IL-27在卵巢癌imAb治疗抵抗中的作用；在此基础上阐明IL-27细胞来源、诱导分泌的调控机制及其介导imAb治疗抵抗的细胞免疫学机制。本课题的完成有望揭示临床中具有重要治疗前景的imAb类药物的治疗抵抗机制，为优化imAb临床使用及提高疗效提供潜在的干预靶点。

免疫调节性抗体（imAb）是一类靶向T细胞表面共信号分子的具有免疫调节功能的蛋白类药物，能够提高机体抗肿瘤免疫应答，在多种实体瘤中显示良好治疗前景。在进展期卵巢癌中，联合imAb治疗后激活的CD8+CTL虽然能够大量杀伤肿瘤细胞，但死亡肿瘤细胞释放的因子如S1P、Gal-1等可诱导DC产生IL-27，DC经IL-27“自我教育”，诱导Tr1、Treg生成，介导负反馈抑制，最终导致肿瘤免疫逃逸。本研究中我们利用IL-27基因敲除小鼠明确IL-27在卵巢癌imAb治疗抵抗中的作用；采用肿瘤细胞上清与DC共培养的方法考察免疫杀伤导致的死亡肿瘤细胞对DC分泌IL-27的诱导效应；利用流式、细胞因子array、PCR-array、体外共培养等方法明确IL-27介导imAb治疗抵抗的免疫机制；最后，评价阻断IL-27增强imAb抗肿瘤效应及机制。最终我们发现在进展期卵巢癌中,IL-27为介导肿瘤抵抗联合免疫调节性抗体治疗的关键效应分子，DC为产生IL-27的细胞来源；并进一步明确了诱导IL-27分泌的分子机制，鉴定鞘氨醇1磷脂酶（S1P）作为诱导DC产生IL-27的“关键因子”。目前正在利用收集的卵巢癌标本评价卵巢癌血液、腹水标本中“S1P”及IL-27水平，分析它们之间的相关性，从而进一步明确本研究发现的临床意义。