RRC ID 36961
著者 Abiko K, Matsumura N, Hamanishi J, Horikawa N, Murakami R, Yamaguchi K, Yoshioka Y, Baba T, Konishi I, Mandai M.
タイトル IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer.
ジャーナル Br J Cancer
Abstract BACKGROUND:PD-L1 (programmed cell death 1 ligand 1) on tumour cells suppresses host immunity through binding to its receptor PD-1 on lymphocytes, and promotes peritoneal dissemination in mouse models of ovarian cancer. However, how PD-L1 expression is regulated in ovarian cancer microenvironment remains unclear.
METHODS:The number of CD8-positive lymphocytes and PD-L1 expression in tumour cells was assessed in ovarian cancer clinical samples. PD-L1 expression and tumour progression in mouse models under conditions of altering IFN-γ signals was assessed.
RESULTS:The number of CD8-positive cells in cancer stroma was very high in peritoneally disseminated tumours, and was strongly correlated to PD-L1 expression on the tumour cells (P<0.001). In mouse models, depleting IFNGR1 (interferon-γ receptor 1) resulted in lower level of PD-L1 expression in tumour cells, increased the number of tumour-infiltrating CD8-positive lymphocytes, inhibition of peritoneal disseminated tumour growth and longer survival (P=0.02). The injection of IFN-γ into subcutaneous tumours induced PD-L1 expression and promoted tumour growth, and PD-L1 depletion completely abrogated tumour growth caused by IFN-γ injection (P=0.01).
CONCLUSIONS:Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth. The lymphocyte infiltration and the IFN-γ status may be the key to effective anti-PD-1 or anti-PD-L1 therapy in ovarian cancer.
巻・号 112(9)
ページ 1501-9
公開日 2015-4-28
DOI 10.1038/bjc.2015.101
PII bjc2015101
PMID 25867264
PMC PMC4453666
MeSH Animals Apoptosis B7-H1 Antigen / metabolism* Blotting, Western CD8-Positive T-Lymphocytes / drug effects CD8-Positive T-Lymphocytes / immunology* CD8-Positive T-Lymphocytes / pathology Cell Proliferation Disease Progression Female Flow Cytometry Humans Immunoenzyme Techniques Interferon-gamma / pharmacology* Lymphocytes, Tumor-Infiltrating / drug effects Lymphocytes, Tumor-Infiltrating / immunology Lymphocytes, Tumor-Infiltrating / pathology Mice Mice, Inbred C57BL Ovarian Neoplasms / drug therapy Ovarian Neoplasms / immunology Ovarian Neoplasms / metabolism* Ovarian Neoplasms / pathology* Peritoneal Neoplasms / drug therapy Peritoneal Neoplasms / immunology Peritoneal Neoplasms / metabolism* Peritoneal Neoplasms / secondary* Prognosis Tumor Cells, Cultured Tumor Microenvironment / drug effects Up-Regulation Xenograft Model Antitumor Assays
IF 5.791
引用数 257
WOS 分野 ONCOLOGY
リソース情報
ヒト・動物細胞 OV2944-HM-1(RCB1483)