Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Institute for Experimental Animals, Advanced Science Research Center, Kanazawa University, Kanazawa, Japan.
Carcinogenesis. 2022 Aug 30;43(7):647-658. doi: 10.1093/carcin/bgac032.
Serous carcinoma of the uterus (USC) is a pathological subtype of high-grade endometrial cancers, with no effective treatment for advanced cases. Since such refractory tumors frequently harbor antitumor immune tolerance, many immunotherapies have been investigated for various malignant tumors using immuno-competent animal models mimicking their local immunities. In this study, we established an orthotopic mouse model of high-grade endometrial cancer and evaluated the local tumor immunity to explore the efficacy of immunotherapies against USC. A multivariate analysis of 62 human USC cases revealed that the tumor-infiltrating cell status, few CD8+ cells and abundant myeloid-derived suppressor cells (MDSCs), was an independent prognostic factor (P < 0.005). A murine endometrial cancer cell (mECC) was obtained from C57BL/6 mice via endometrium-specific deletion of Pten and Tp53, and another high-grade cell (HPmECC) was established by further overexpressing Myc in mECCs. HPmECCs exhibited higher capacities of migration and anchorage-independent proliferation than mECCs (P < 0.01, P < 0.0001), and when both types of cells were inoculated into the uterus of C57BL/6 mice, the prognosis of mice bearing HPmECC-derived tumors was significantly poorer (P < 0.001). Histopathological analysis of HPmECC orthotopic tumors showed serous carcinoma-like features with prominent tumor infiltration of MDSCs (P < 0.05), and anti-Gr-1 antibody treatment significantly prolonged the prognosis of HPmECC-derived tumor-bearing mice (P < 0.05). High CCL7 expression was observed in human USC and HPmECC, and MDSCs migration was promoted in a CCL7 concentration-dependent manner. These results indicate that antitumor immunity is suppressed in USC due to increased number of tumor-infiltrating MDSCs via CCL signal.
子宫浆液性癌（USC）是高级别子宫内膜癌的一种病理亚型，对于晚期病例尚无有效治疗方法。由于这些难治性肿瘤常存在抗肿瘤免疫耐受，因此许多免疫疗法已在使用免疫活性动物模型来研究各种恶性肿瘤，这些模型模拟了其局部免疫。在这项研究中，我们建立了高级别子宫内膜癌的原位小鼠模型，并评估了局部肿瘤免疫，以探索免疫疗法治疗 USC 的疗效。对 62 例人 USC 病例的多变量分析表明，肿瘤浸润细胞状态，即 CD8+细胞少且髓系来源抑制细胞（MDSCs）丰富，是一个独立的预后因素（P<0.005）。我们从 C57BL/6 小鼠的子宫内膜中通过特异性缺失 Pten 和 Tp53 获得了一种小鼠子宫内膜癌细胞（mECC），并通过在 mECC 中进一步过表达 Myc 建立了另一种高级别细胞（HPmECC）。与 mECC 相比，HPmECC 具有更高的迁移和无锚定增殖能力（P<0.01，P<0.0001），当将这两种细胞接种到 C57BL/6 小鼠的子宫中时，携带 HPmECC 衍生肿瘤的小鼠的预后明显更差（P<0.001）。HPmECC 原位肿瘤的组织病理学分析显示出类似于浆液性癌的特征，MDSC 明显浸润肿瘤（P<0.05），并且抗 Gr-1 抗体治疗显著延长了 HPmECC 衍生肿瘤荷瘤小鼠的预后（P<0.05）。人 USC 和 HPmECC 中均观察到 CCL7 表达升高，MDSC 迁移呈 CCL7 浓度依赖性增加。这些结果表明，由于肿瘤浸润 MDSC 的数量增加，通过 CCL 信号抑制了 USC 中的抗肿瘤免疫。
