RRC ID 71923
著者 Mise Y, Hamanishi J, Daikoku T, Takamatsu S, Miyamoto T, Taki M, Yamanoi K, Yamaguchi K, Ukita M, Horikawa N, Abiko K, Murakami R, Furutake Y, Hosoe Y, Terakawa J, Kagabu M, Sugai T, Osakabe M, Fujiwara H, Matsumura N, Mandai M, Baba T.
タイトル Immunosuppressive tumor microenvironment in uterine serous carcinoma via CCL7 signal with myeloid-derived suppressor cells.
ジャーナル Carcinogenesis
Abstract 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 anti-tumor 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 anti-tumor immunity is suppressed in USC due to increased number of tumor-infiltrating MDSCs via CCL signal.
巻・号 43(7)
ページ 647-658
公開日 2022-8-30
DOI 10.1093/carcin/bgac032
PII 6556146
PMID 35353883
MeSH Animals Cell Line, Tumor Chemokine CCL7 Cystadenocarcinoma, Serous* / pathology Endometrial Neoplasms* / pathology Female Humans Mice Mice, Inbred C57BL Myeloid-Derived Suppressor Cells* Tumor Microenvironment
IF 4.603
リソース情報
遺伝子材料 pCAGIPuro-FlagmcMycWT (RDB14100) pCAGIPuro-HAmcMyc_DN143 (RDB14101)